Updated on 2023/05/11

写真a

 
NISHIYAMA KAZUHIRO
 
Organization
Graduate School of Veterinary Science Department of Veterinary Science Associate Professor
School of Veterinary Science Department of Veterinary Science
Title
Associate Professor
Affiliation
Institute of Veterinary Science
Contact information
メールアドレス
Affiliation campus
Rinku Campus

Position

  • Graduate School of Veterinary Science Department of Veterinary Science 

    Associate Professor  2023.04 - Now

  • School of Veterinary Science Department of Veterinary Science 

    Associate Professor  2023.04 - Now

Degree

  • 博士(獣医学) ( Osaka Prefecture University )

  • 学士(獣医学) ( Osaka Prefecture University )

Research Areas

  • Life Science / Pharmacology

Awards

  • 第2回 米田幸雄賞

    2023.03   予防薬理学研究所  

  • 第38回学術奨励賞

    2022.12   日本薬理学会  

  • YIA

    2022.10   第12回国際NO学会  

  • YIA

    2022.07   第51回 日本心脈管作動物質学会  

  • Young Investigation Awards

    2021.12   第31回 日本循環薬理学会  

  • 第1回 若手シンポジウム 優秀賞

    2021.11   レドックスR&D戦略委員会   システイン修飾を介した GPCR の内在化機構の解明

  • Young Investigation Awards最優秀賞

    2021.05   第21回日本NO学会学術集会  

  • YIA

    2021.03   SFRRI (Society for Free Radical Research International) 2021  

  • 獣医学奨励賞

    西山 和宏

    2019.09   日本獣医学会  

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Job Career (off-campus)

  • Osaka Metropolitan University   Graduate School of Veterinary Science

    2023.04 - Now

  • 九州大学大学院   薬学研究院   講師

    2020.11 - 2023.03

  • 九州大学大学院   薬学研究院   特任助教

    2017.06 - 2020.10

Papers

  • Knockout of Purinergic P2Y6 Receptor Fails to Improve Liver Injury and Inflammation in Non-Alcoholic Steatohepatitis.

    Kazuhiro Nishiyama, Kohei Ariyoshi, Akiyuki Nishimura, Yuri Kato, Xinya Mi, Hitoshi Kurose, Sang Geon Kim, Motohiro Nishida

    International journal of molecular sciences   24 ( 4 )   2023.02

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Nonalcoholic steatohepatitis (NASH) is a disease that progresses from nonalcoholic fatty liver (NAFL) and which is characterized by inflammation and fibrosis. The purinergic P2Y6 receptor (P2Y6R) is a pro-inflammatory Gq/G12 family protein-coupled receptor and reportedly contributes to intestinal inflammation and cardiovascular fibrosis, but its role in liver pathogenesis is unknown. Human genomics data analysis revealed that the liver P2Y6R mRNA expression level is increased during the progression from NAFL to NASH, which positively correlates with inductions of C-C motif chemokine 2 (CCL2) and collagen type I α1 chain (Col1a1) mRNAs. Therefore, we examined the impact of P2Y6R functional deficiency in mice crossed with a NASH model using a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Feeding CDAHFD for 6 weeks markedly increased P2Y6R expression level in mouse liver, which was positively correlated with CCL2 mRNA induction. Unexpectedly, the CDAHFD treatment for 6 weeks increased liver weights with severe steatosis in both wild-type (WT) and P2Y6R knockout (KO) mice, while the disease marker levels such as serum AST and liver CCL2 mRNA in CDAHFD-treated P2Y6R KO mice were rather aggravated compared with those of CDAHFD-treated WT mice. Thus, P2Y6R may not contribute to the progression of liver injury, despite increased expression in NASH liver.

    DOI: 10.3390/ijms24043800

    PubMed

  • Echinochrome Prevents Sulfide Catabolism-Associated Chronic Heart Failure after Myocardial Infarction in Mice.

    Xiaokang Tang, Akiyuki Nishimura, Kohei Ariyoshi, Kazuhiro Nishiyama, Yuri Kato, Elena A Vasileva, Natalia P Mishchenko, Sergey A Fedoreyev, Valentin A Stonik, Hyoung-Kyu Kim, Jin Han, Yasunari Kanda, Keitaro Umezawa, Yasuteru Urano, Takaaki Akaike, Motohiro Nishida

    Marine drugs   21 ( 1 )   2023.01

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Abnormal sulfide catabolism, especially the accumulation of hydrogen sulfide (H2S) during hypoxic or inflammatory stresses, is a major cause of redox imbalance-associated cardiac dysfunction. Polyhydroxynaphtoquinone echinochrome A (Ech-A), a natural pigment of marine origin found in the shells and needles of many species of sea urchins, is a potent antioxidant and inhibits acute myocardial ferroptosis after ischemia/reperfusion, but the chronic effect of Ech-A on heart failure is unknown. Reactive sulfur species (RSS), which include catenated sulfur atoms, have been revealed as true biomolecules with high redox reactivity required for intracellular energy metabolism and signal transduction. Here, we report that continuous intraperitoneal administration of Ech-A (2.0 mg/kg/day) prevents RSS catabolism-associated chronic heart failure after myocardial infarction (MI) in mice. Ech-A prevented left ventricular (LV) systolic dysfunction and structural remodeling after MI. Fluorescence imaging revealed that intracellular RSS level was reduced after MI, while H2S/HS- level was increased in LV myocardium, which was attenuated by Ech-A. This result indicates that Ech-A suppresses RSS catabolism to H2S/HS- in LV myocardium after MI. In addition, Ech-A reduced oxidative stress formation by MI. Ech-A suppressed RSS catabolism caused by hypoxia in neonatal rat cardiomyocytes and human iPS cell-derived cardiomyocytes. Ech-A also suppressed RSS catabolism caused by lipopolysaccharide stimulation in macrophages. Thus, Ech-A has the potential to improve chronic heart failure after MI, in part by preventing sulfide catabolism.

    DOI: 10.3390/md21010052

    PubMed

  • L-arginine-induced pancreatitis aggravated by inhibiting Na<sup>+</sup>/Ca<sup>2+</sup> exchanger 1

    ONO Naoshige, HORIKOSHI Joji, IZAWA Takeshi, NISHIYAMA Kazuhiro, TANAKA Miyuu, KUWAMURA Mitsuru, AZUMA Yasu-Taka

    Journal of Veterinary Medical Science   advpub ( 0 )   2023( ISSN:09167250

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    <p>Na<sup>+</sup>/Ca<sup>2+</sup> exchangers (NCX) are an exchange transporter of Na<sup>+</sup> and Ca<sup>2+</sup> ions on the plasma membrane. There are three types of NCX: NCX1, NCX2, and NCX3. We have been working for many years to understand the role of NCX1 and NCX2 in gastrointestinal motility. In this study, we focused on the pancreas, an organ closely related to the gastrointestinal tract, and used a mouse model of acute pancreatitis to investigate a possible role for NCX1 in the pathogenesis of pancreatitis. We characterized a model of acute pancreatitis induced by excessive doses of L-arginine. We administered the NCX1 inhibitor SEA0400 (1 mg/kg) 1 hr prior to L-arginine-induced pancreatitis and evaluated pathological changes. Mice treated with NCX1 inhibitors show exacerbation of the disease with decreased survival and increased amylase activity in response to L-arginine-induced experimental acute pancreatitis, and this exacerbation correlates with increased autophagy mediated by LC3B and p62. These results suggest that NCX1 has a role in regulating pancreatic inflammation and acinar cell homeostasis.</p>

    DOI: 10.1292/jvms.22-0569

    PubMed

  • TRPC3-Nox2 Protein Complex Formation Increases the Risk of SARS-CoV-2 Spike Protein-Induced Cardiomyocyte Dysfunction through ACE2 Upregulation.

    Yuri Kato, Kazuhiro Nishiyama, Jae Man Lee, Yuko Ibuki, Yumiko Imai, Takamasa Noda, Noriho Kamiya, Takahiro Kusakabe, Yasunari Kanda, Motohiro Nishida

    International journal of molecular sciences   24 ( 1 )   2022.12

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Myocardial damage caused by the newly emerged coronavirus (SARS-CoV-2) infection is one of the key determinants of COVID-19 severity and mortality. SARS-CoV-2 entry to host cells is initiated by binding with its receptor, angiotensin-converting enzyme (ACE) 2, and the ACE2 abundance is thought to reflect the susceptibility to infection. Here, we report that ibudilast, which we previously identified as a potent inhibitor of protein complex between transient receptor potential canonical (TRPC) 3 and NADPH oxidase (Nox) 2, attenuates the SARS-CoV-2 spike glycoprotein pseudovirus-evoked contractile and metabolic dysfunctions of neonatal rat cardiomyocytes (NRCMs). Epidemiologically reported risk factors of severe COVID-19, including cigarette sidestream smoke (CSS) and anti-cancer drug treatment, commonly upregulate ACE2 expression level, and these were suppressed by inhibiting TRPC3-Nox2 complex formation. Exposure of NRCMs to SARS-CoV-2 pseudovirus, as well as CSS and doxorubicin (Dox), induces ATP release through pannexin-1 hemi-channels, and this ATP release potentiates pseudovirus entry to NRCMs and human iPS cell-derived cardiomyocytes (hiPS-CMs). As the pseudovirus entry followed by production of reactive oxygen species was attenuated by inhibiting TRPC3-Nox2 complex in hiPS-CMs, we suggest that TRPC3-Nox2 complex formation triggered by panexin1-mediated ATP release participates in exacerbation of myocardial damage by amplifying ACE2-dependent SARS-CoV-2 entry.

    DOI: 10.3390/ijms24010102

    PubMed

  • Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors.

    Sayaka Oda, Kazuhiro Nishiyama, Yuka Furumoto, Yohei Yamaguchi, Akiyuki Nishimura, Xiaokang Tang, Yuri Kato, Takuro Numaga-Tomita, Toshiyuki Kaneko, Supachoke Mangmool, Takuya Kuroda, Reishin Okubo, Makoto Sanbo, Masumi Hirabayashi, Yoji Sato, Yasuaki Nakagawa, Koichiro Kuwahara, Ryu Nagata, Gentaro Iribe, Yasuo Mori, Motohiro Nishida

    Nature communications   13 ( 1 )   6374 - 6374   2022.10

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Baroreflex control of cardiac contraction (positive inotropy) through sympathetic nerve activation is important for cardiocirculatory homeostasis. Transient receptor potential canonical subfamily (TRPC) channels are responsible for α1-adrenoceptor (α1AR)-stimulated cation entry and their upregulation is associated with pathological cardiac remodeling. Whether TRPC channels participate in physiological pump functions remains unclear. We demonstrate that TRPC6-specific Zn2+ influx potentiates β-adrenoceptor (βAR)-stimulated positive inotropy in rodent cardiomyocytes. Deletion of trpc6 impairs sympathetic nerve-activated positive inotropy but not chronotropy in mice. TRPC6-mediated Zn2+ influx boosts α1AR-stimulated βAR/Gs-dependent signaling in rat cardiomyocytes by inhibiting β-arrestin-mediated βAR internalization. Replacing two TRPC6-specific amino acids in the pore region with TRPC3 residues diminishes the α1AR-stimulated Zn2+ influx and positive inotropic response. Pharmacological enhancement of TRPC6-mediated Zn2+ influx prevents chronic heart failure progression in mice. Our data demonstrate that TRPC6-mediated Zn2+ influx with α1AR stimulation enhances baroreflex-induced positive inotropy, which may be a new therapeutic strategy for chronic heart failure.

    DOI: 10.1038/s41467-022-34194-9

    PubMed

  • Cystine-dependent antiporters buffer against excess intracellular reactive sulfur species-induced stress.

    Masahiro Akiyama, Takamitsu Unoki, Hanako Aoki, Akiyuki Nishimura, Yasuhiro Shinkai, Eiji Warabi, Kazuhiro Nishiyama, Yuka Furumoto, Naohiko Anzai, Takaaki Akaike, Motohiro Nishida, Yoshito Kumagai

    Redox biology   57   102514 - 102514   2022.10

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Reactive sulfur species (RSS) play a role in redox homeostasis; however, adaptive cell responses to excessive intracellular RSS are not well understood. Therefore, in this study, we generated transgenic (Tg) mice overexpressing cystathionine gamma-lyase (CSE) to produce excessive RSS. Contrary to expectations, tissue concentrations of RSS, such as cysteine persulfide (CysSSH), were comparable in both wild-type and CSE Tg mice, but the plasma concentrations of CysSSH were significantly higher in CSE Tg mice than in wild-type mice. This export of surplus intracellular RSS was also observed in primary hepatocytes of CSE Tg mice. Exposure of primary hepatocytes to the RSS generator sodium tetrasulfide (Na2S4) resulted in an initial increase in the intracellular concentration of RSS, which later returned to basal levels after export into the extracellular space. Interestingly, among all amino acids, cystine (CysSSCys) was found to be essential for CysSSH export from primary mouse hepatocytes, HepG2 cells, and HEK293 cells during Na2S4 exposure, suggesting that the cystine/glutamate transporter (SLC7A11) contributes, at least partially, to CysSSH export. We established HepG2 cell lines with knockout and overexpression of SLC7A11 and used them to confirm SLC7A11 as the predominant antiporter of CysSSCys and CysSSH. We observed that the poor efflux of excess CysSSH from the cell enhanced cellular stresses induced by Na2S4 exposure, such as polysulfidation of intracellular proteins, mitochondrial damage, and cytotoxicity. These results suggest the presence of a cellular response to excess intracellular RSS that involves the extracellular efflux of excess CysSSH by a cystine-dependent transporter to maintain intracellular redox homeostasis.

    DOI: 10.1016/j.redox.2022.102514

    PubMed

  • Inhibition of transient receptor potential cation channel 6 promotes capillary arterialization during post-ischaemic blood flow recovery.

    Takuro Numaga-Tomita, Tsukasa Shimauchi, Yuri Kato, Kazuhiro Nishiyama, Akiyuki Nishimura, Kosuke Sakata, Hiroyuki Inada, Satomi Kita, Takahiro Iwamoto, Junichi Nabekura, Lutz Birnbaumer, Yasuo Mori, Motohiro Nishida

    British journal of pharmacology   2022.09

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    BACKGROUND AND PURPOSE: Capillary arterialization, characterized by the coverage of pre-existing or nascent capillary vessels with vascular smooth muscle cells (VSMCs), is critical for the development of collateral arterioles to improve post-ischaemic blood flow. We previously demonstrated that the inhibition of transient receptor potential 6 subfamily C, member 6 (TRPC6) channels facilitate contractile differentiation of VSMCs under ischaemic stress. We here investigated whether TRPC6 inhibition promotes post-ischaemic blood flow recovery through capillary arterialization in vivo. EXPERIMENTAL APPROACH: Mice were subjected to hindlimb ischaemia by ligating left femoral artery. The recovery rate of peripheral blood flow was calculated by the ratio of ischaemic left leg to non-ischaemic right one. The number and diameter of blood vessels were analysed by immunohistochemistry. Expression and phosphorylation levels of TRPC6 proteins were determined by western blotting and immunohistochemistry. KEY RESULTS: Although the post-ischaemic blood flow recovery is reportedly dependent on endothelium-dependent relaxing factors, systemic TRPC6 deletion significantly promoted blood flow recovery under the condition that nitric oxide or prostacyclin production were inhibited, accompanying capillary arterialization. Cilostazol, a clinically approved drug for peripheral arterial disease, facilitates blood flow recovery by inactivating TRPC6 via phosphorylation at Thr69 in VSMCs. Furthermore, inhibition of TRPC6 channel activity by pyrazole-2 (Pyr2; BTP2; YM-58483) promoted post-ischaemic blood flow recovery in Apolipoprotein E-knockout mice. CONCLUSION AND IMPLICATIONS: Suppression of TRPC6 channel activity in VSMCs could be a new strategy for the improvement of post-ischaemic peripheral blood circulation.

    DOI: 10.1111/bph.15942

    PubMed

  • Drug repurposing for the treatment of COVID-19.

    Yuri Kato, Kazuhiro Nishiyama, Akiyuki Nishimura, Takamasa Noda, Kaori Okabe, Takahiro Kusakabe, Yasunari Kanda, Motohiro Nishida

    Journal of pharmacological sciences   149 ( 3 )   108 - 114   2022.07

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:Domestic journal  

    Coronavirus disease 2019 (COVID-19) remains prevalent worldwide since its onset was confirmed in Wuhan, China in 2019. Vaccines against the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have shown a preventive effect against the onset and severity of COVID-19, and social and economic activities are gradually recovering. However, the presence of vaccine-resistant variants has been reported, and the development of therapeutic agents for patients with severe COVID-19 and related sequelae remains urgent. Drug repurposing, also called drug repositioning or eco-pharma, is the strategy of using previously approved and safe drugs for a therapeutic indication that is different from their original indication. The risk of severe COVID-19 and mortality increases with advancing age, cardiovascular disease, hypertension, diabetes, and cancer. We have reported three protein-protein interactions that are related to heart failure, and recently identified that one mechanism increases the risk of SARS-CoV-2 infection in mammalian cells. This review outlines the global efforts and outcomes of drug repurposing research for the treatment of severe COVID-19. It also discusses our recent finding of a new protein-protein interaction that is common to COVID-19 aggravation and heart failure.

    DOI: 10.1016/j.jphs.2022.04.007

    PubMed

  • A TRPC3/6 Channel Inhibitor Promotes Arteriogenesis after Hind-Limb Ischemia.

    Tsukasa Shimauchi, Takuro Numaga-Tomita, Yuri Kato, Hiroyuki Morimoto, Kosuke Sakata, Ryosuke Matsukane, Akiyuki Nishimura, Kazuhiro Nishiyama, Atsushi Shibuta, Yutoku Horiuchi, Hitoshi Kurose, Sang Geon Kim, Yasuteru Urano, Takashi Ohshima, Motohiro Nishida

    Cells   11 ( 13 )   2022.06

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Retarded revascularization after progressive occlusion of large conductance arteries is a major cause of bad prognosis for peripheral artery disease (PAD). However, pharmacological treatment for PAD is still limited. We previously reported that suppression of transient receptor potential canonical (TRPC) 6 channel activity in vascular smooth muscle cells (VSMCs) facilitates VSMC differentiation without affecting proliferation and migration. In this study, we found that 1-benzilpiperadine derivative (1-BP), a selective inhibitor for TRPC3 and TRPC6 channel activities, induced VSMC differentiation. 1-BP-treated mice showed increased capillary arterialization and improvement of peripheral circulation and skeletal muscle mass after hind-limb ischemia (HLI) in mice. 1-BP had no additive effect on the facilitation of blood flow recovery after HLI in TRPC6-deficient mice, suggesting that suppression of TRPC6 underlies facilitation of the blood flow recovery by 1-BP. 1-BP also improved vascular nitric oxide bioavailability and blood flow recovery after HLI in hypercholesterolemic mice with endothelial dysfunction, suggesting the retrograde interaction from VSMCs to endothelium. These results suggest that 1-BP becomes a potential seed for PAD treatments that target vascular TRPC6 channels.

    DOI: 10.3390/cells11132041

    PubMed

  • Redox-dependent internalization of the purinergic P2Y6 receptor limits colitis progression.

    Kazuhiro Nishiyama, Akiyuki Nishimura, Kakeru Shimoda, Tomohiro Tanaka, Yuri Kato, Takahiro Shibata, Hiroshi Tanaka, Hitoshi Kurose, Yasu-Taka Azuma, Hideshi Ihara, Yoshito Kumagai, Takaaki Akaike, Philip Eaton, Koji Uchida, Motohiro Nishida

    Science signaling   15 ( 716 )   eabj0644   2022.01

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    [Figure: see text].

    DOI: 10.1126/scisignal.abj0644

    PubMed

  • IL-19 Contributes to the Development of Nonalcoholic Steatohepatitis by Altering Lipid Metabolism

    Yasu-Taka Azuma, Takashi Fujita, Takeshi Izawa, Kana Hirota, Kazuhiro Nishiyama, Airi Ikegami, Tomoko Aoyama, Mikihito Ike, Yumi Ushikai, Mitsuru Kuwamura, Hideki Fujii, Koichi Tsuneyama

    Cells   10 ( 12 )   2021.12

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Interleukin (IL)-19, a member of the IL-10 family, is an anti-inflammatory cytokine produced primarily by macrophages. Nonalcoholic steatohepatitis (NASH) is a disease that has progressed from nonalcoholic fatty liver disease (NAFLD) and is characterized by inflammation and fibrosis. We evaluated the functions of IL-19 in a NAFLD/NASH mouse model using a 60% high fat diet with 0.1% methionine, without choline, and with 2% cholesterol (CDAHFD). Wild-type (WT) and IL-19 gene-deficient (KO) mice were fed a CDAHFD or standard diet for 9 weeks. Liver injury, inflammation, and fibrosis induced by CDAHFD were significantly worse in IL-19 KO mice than in WT mice. IL-6, TNF-α, and TGF-β were significantly higher in IL-19 KO mice than in WT mice. As a mechanism using an in vitro experiment, palmitate-induced triglyceride and cholesterol contents were decreased by the addition of IL-19 in HepG2 cells. Furthermore, addition of IL-19 decreased the expression of fatty acid synthesis-related enzymes and increased ATP content in HepG2 cells. The action of IL-19 in vitro suppressed lipid metabolism. In conclusion, IL-19 may play an important role in the development of steatosis and fibrosis by directly regulating liver metabolism and may be a potential target for the treatment of liver diseases.

    DOI: 10.3390/cells10123513

    PubMed

  • TRPC3-Nox2複合体形成と筋ジストロフィー治療への応用

    西山 和宏

    上原記念生命科学財団研究報告集   35   1 - 4   2021.12

  • Structural library and visualization of endogenously oxidized phosphatidylcholines using mass spectrometry-based techniques.

    Yuta Matsuoka, Masatomo Takahashi, Yuki Sugiura, Yoshihiro Izumi, Kazuhiro Nishiyama, Motohiro Nishida, Makoto Suematsu, Takeshi Bamba, Ken-Ichi Yamada

    Nature communications   12 ( 1 )   6339 - 6339   2021.11

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Although oxidized phosphatidylcholines (oxPCs) play critical roles in numerous pathological events, the type and production sites of endogenous oxPCs remain unknown because of the lack of structural information and dedicated analytical methods. Herein, a library of 465 oxPCs is constructed using high-resolution mass spectrometry-based non-targeted analytical methods and employed to detect 70 oxPCs in mice with acetaminophen-induced acute liver failure. We show that doubly oxygenated polyunsaturated fatty acid (PUFA)-PCs (PC PUFA;O2), containing epoxy and hydroxide groups, are generated in the early phase of liver injury. Hybridization with in-vivo 18O labeling and matrix-assisted laser desorption/ionization-tandem MS imaging reveals that PC PUFA;O2 are accumulated in cytochrome P450 2E1-expressing and glutathione-depleted hepatocytes, which are the major sites of liver injury. The developed library and visualization methodology should facilitate the characterization of specific lipid peroxidation events and enhance our understanding of their physiological and pathological significance in lipid peroxidation-related diseases.

    DOI: 10.1038/s41467-021-26633-w

    PubMed

  • ストレスによる消化管運動の変化は特異的一過性受容体電位チャネルを介した平滑筋収縮に関連する(Gastrointestinal motility modulation by stress is associated with reduced smooth muscle contraction through specific transient receptor potential channel)

    Azuma Yasu-taka, Suzuki Sho, Nishiyama Kazuhiro, Yamaguchi Taro

    The Journal of Veterinary Medical Science   83 ( 4 )   622 - 629   2021.04( ISSN:0916-7250

  • Deletion of TRPC3 or TRPC6 Fails to Attenuate the Formation of Inflammation and Fibrosis in Non-alcoholic Steatohepatitis. Reviewed

    Kazuhiro Nishiyama, Chiemi Toyama, Yuri Kato, Tomohiro Tanaka, Akiyuki Nishimura, Ryu Nagata, Yasuo Mori, Motohiro Nishida

    Biological & pharmaceutical bulletin   44 ( 3 )   431 - 436   2021.03

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    Authorship:Lead author   Publishing type:Research paper (scientific journal)   International / domestic magazine:Domestic journal  

    Non-alcoholic steatohepatitis (NASH) is a disease that has progressed from non-alcoholic fatty liver disease (NAFLD) and is characterized by inflammation and fibrosis. Two transient receptor potential canonical (TRPC) subfamily members, TRPC3 and TRPC6 (TRPC3/6), reportedly participate in the development of fibrosis in cardiovascular and renal systems. We hypothesized that TRPC3/6 may also participate in NASH fibrosis. We evaluated the effects of TRPC3 or TRPC6 functional deficiency in a NASH mouse model using choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Wild-type (WT) and TRPC3 or TRPC6 gene-deficient (KO) mice were fed with CDAHFD or standard diet for 6 weeks. The CDAHFD-induced body weight loss in TRPC6 KO mice was significantly lower compared with WT mice with CDAHFD. CDAHFD treatment significantly increased TRPC3 mRNA expression level and tissue weight in WT liver, which were suppressed in TRPC3 KO mice. However, either systemic deletion of TRPC3 or TRPC6 failed to attenuate liver steatosis, inflammation and fibrosis. These results imply that TRPC3 and TRPC6 are unlikely to be involved in liver dysfunction and fibrosis of NASH model mice.

    DOI: 10.1248/bpb.b20-00903

    PubMed

  • TRPC3またはTRPC6の欠失は非アルコール性脂肪性肝炎における炎症および線維症の発症を軽減しない(Deletion of TRPC3 or TRPC6 Fails to Attenuate the Formation of Inflammation and Fibrosis in Non-alcoholic Steatohepatitis)

    Nishiyama Kazuhiro, Toyama Chiemi, Kato Yuri, Tanaka Tomohiro, Nishimura Akiyuki, Nagata Ryu, Mori Yasuo, Nishida Motohiro

    Biological & Pharmaceutical Bulletin   44 ( 3 )   431 - 436   2021.03( ISSN:0918-6158

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    Transient receptor potential canonical(TRPC)3/6は非アルコール性脂肪性肝炎(NASH)線維症に関与していると考え、コリン欠乏高脂肪食(CDAHFD)を用いて、NASHモデルマウスにおけるTRPC3またはTRPC6の機能欠損の影響を調べた。野生型(WT)およびTRPC3またはTRPC6遺伝子欠損(KO)マウスに、CDAHFDまたは標準食を6週間与えた。CDAHFDによる体重減少は、TRPC6KOマウスでWTマウスより有意に少なかった。CDAHFD投与により、WTマウスの肝臓におけるTRPC3mRNA発現レベルと組織重量は有意に増加したが、TRPC3KOマウスでは抑制された。しかし、TRPC3またはTRPC6の欠失は、脂肪肝、炎症および線維症の発症を軽減しなかった。以上より、TRPC3/6がNASHモデルマウスの肝機能障害や線維症に関与する可能性は低いと考えられた。

  • Gastrointestinal motility modulation by stress is associated with reduced smooth muscle contraction through specific transient receptor potential channel. Reviewed

    Yasu-Taka Azuma, Sho Suzuki, Kazuhiro Nishiyama, Taro Yamaguchi

    The Journal of veterinary medical science   2021.02

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:Domestic journal  

    Excessive stress response causes disability in social life. There are many diseases caused by stress, such as gastrointestinal motility disorders, depression, eating disorders, and cardiovascular diseases. Transient receptor potential (TRP) channels underlie non-selective cation currents and are downstream effectors of G protein-coupled receptors. Ca2+ influx is important for smooth muscle contraction, which is responsible for gastrointestinal motility. Little is known about the possible involvement of TRP channels in the gastrointestinal motility disorders due to stress. The purpose of this study was to measure the changes in gastrointestinal motility caused by stress and to elucidate the mechanism of these changes. The stress model used the water immersion restraint stress. Gastrointestinal motility, especially the ileum, was recorded responses to electric field stimulation (EFS) by isometric transducer. EFS-induced contraction was significantly reduced in the ileum of stressed mouse. Even under the conditions treated with atropine, EFS-induced contraction was significantly reduced in the ileum of stressed mouse. In addition, carbachol-induced, neurokinin A-induced, and substance P-induced contractions were all significantly reduced in the ileum of stressed mouse. Furthermore, the expression of TRPC3 was decreased in the ileum of stressed mouse. These results suggest that the gastrointestinal motility disorders due to stress is associated with specific non-selective cation channel.

    DOI: 10.1292/jvms.20-0490

    PubMed

  • Modulation of P2Y6R expression exacerbates pressure overload-induced cardiac remodeling in mice. Reviewed

    Kakeru Shimoda, Akiyuki Nishimura, Caroline Sunggip, Tomoya Ito, Kazuhiro Nishiyama, Yuri Kato, Tomohiro Tanaka, Hidetoshi Tozaki-Saitoh, Makoto Tsuda, Motohiro Nishida

    Scientific reports   10 ( 1 )   13926 - 13926   2020.08

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y6 receptor (P2Y6R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y6R prevents or promotes heart failure. We demonstrate that inhibition of P2Y6R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y6R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y6R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y6R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y6R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y6R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y6R exacerbates pressure overload-induced heart failure in mice, although P2Y6R in cardiomyocytes contributes to the progression of cardiac fibrosis.

    DOI: 10.1038/s41598-020-70956-5

    PubMed

  • BALB/cマウスにおいてインターロイキン19はリポ多糖類誘発性のサイトカイン産生を増強し、polyl:C誘発性サイトカイン産生を抑制する(Interleukin-19 enhances cytokine production induced by lipopolysaccharide and inhibits cytokine production induced by polyl:C in BALB/c mice)

    Azuma Yasu-taka, Nishiyama Kazuhiro

    The Journal of Veterinary Medical Science   82 ( 7 )   891 - 896   2020.07( ISSN:0916-7250

  • Interleukin-19 enhances cytokine production induced by lipopolysaccharide and inhibits cytokine production induced by polyI:C in BALB/c mice. Reviewed

    Yasu-Taka Azuma, Kazuhiro Nishiyama

    The Journal of veterinary medical science   2020.05

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    International / domestic magazine:Domestic journal  

    Interleukin (IL)-19 is a cytokine of the IL-10 family. There are many reports on the involvement of IL-19 in several human diseases. There also are many reports elucidating the role of IL-19 using mouse disease models. Most reports use C57BL/6 mice, whereas few reports use BALB/c mice, in terms of the mouse disease model that the researchers used in the present study. To date, research on the role of IL-19 is diversified, yet some basic mechanisms are still unclear. In this study, we administered lipopolysaccharide (LPS), polyI:C, and CpG to BALB/c mice, measured more than 20 cytokines in the blood and compared them with that of the wild-type and IL-19-deficient (IL-19 KO) mice. LPS is associated with bacterial infection, polyI:C is associated with viral infection, and CpG is associated with both bacterial and viral infections. Among the cytokines measured, the results of experiments using LPS revealed that the production of some cytokines was suppressed in IL-19 KO mice. Interestingly, the experiments using polyI:C revealed that production of some cytokines was enhanced in IL-19 KO mice. However, the experiments using CpG have shown that the production of only one cytokine was enhanced in IL-19 KO mice. These results revealed that cytokine production in the blood was regulated by IL-19, and the type of regulation was dependent on the administered stimulant.

    DOI: 10.1292/jvms.20-0137

    PubMed

  • TRPC3-based protein signaling complex as a therapeutic target of myocardial atrophy. Reviewed

    Kazuhiro Nishiyama, Tomohiro Tanaka, Akiyuki Nishimura, Motohiro Nishida

    Current molecular pharmacology   2020.04

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    International / domestic magazine:International journal  

    BACKGROUND: Transient receptor potential (TRP) channels, especially canonical TRP channel subfamily members 3 (TRPC3) and 6 (TRPC6), have attracted attention as a putative therapeutic target of heart | 1 failure. Moreover, TRPC3 and TRPC6 channels are physiologically important for maintaining cellular homeostasis. How TRPC3/C6 channels alter intracellular signaling from adaptation to maladaptation has been discussed for many years. We recently showed that formation of a protein signal complex between TRPC3 and NADPH oxidase (Nox) 2 caused by environmental stresses (e.g., hypoxia, nutritional deficiency, and anticancer drug treatment) promotes Nox2-dependent reactive oxygen species production and cardiac stiffness, including myocardial atrophy and interstitial fibrosis, in rodents. In fact, pharmacological prevention of the TRPC3-Nox2 protein complex can maintain cardiac flexibility in mice after anti-cancer drug treatment. CONCLUSION: In this mini-review, we discuss the relationship between TRPC3/C6 channels and cardiovascular disease, and propose a new therapeutic strategy by focusing on pathology-specific protein- protein interactions.

    DOI: 10.2174/1874467213666200407090121

    PubMed

  • Mitochondrial dynamics in exercise physiology Reviewed

    Tanaka, T., Nishimura, A., Nishiyama, K., Goto, T., Numaga-Tomita, T., Nishida, M.

    Pflugers Archiv European Journal of Physiology   472 ( 2 )   2020.01( ISSN:0031-6768

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    A growing body of evidence suggests that exercise shows pleiotropic effects on the maintenance of systemic homeostasis through mitochondria. Dysregulation of mitochondrial dynamism is associated with metabolic inflexibility, resulting in many of the metabolic diseases and aging. Studies have suggested that exercise prevents and delays the progression of mitochondrial dysfunction by improving mitochondrial metabolism, biogenesis, and quality control. Exercise modulates functions of mitochondrial dynamics-regulating proteins through post-translational modification mechanisms. In this review, we discuss the putative mechanisms underlying maintenance of mitochondrial homeostasis by exercise, especially focusing on the post-translational modifications of several signaling proteins contributing to mitochondrial biogenesis, autophagy or mitophagy flux, and fission/fusion cycle. We also introduce novel small molecules that can potentially mimic exercise therapy through preserving mitochondrial dynamism. These recent advancements in the field of mitochondrial biology may lead to a greater understanding of exercise signaling.

    DOI: 10.1007/s00424-019-02258-3

    PubMed

  • Canonical Transient Receptor Potential Channels and Vascular Smooth Muscle Cell Plasticity Reviewed

    Motohiro Nishida, Tomohiro Tanaka, Supachoke Mangmool, Kazuhiro Nishiyama, Akiyuki Nishimura

    Journal of Lipid and Atherosclerosis   9 ( 1 )   124 - 124   2020.01

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    Publishing type:Research paper (scientific journal)  

    DOI: 10.12997/jla.2020.9.1.124

  • TRPC6 regulates phenotypic switching of vascular smooth muscle cells through plasma membrane potential-dependent coupling with PTEN Reviewed

    Numaga-Tomita, T., Shimauchi, T., Oda, S., Tanaka, T., Nishiyama, K., Nishimura, A., Birnbaumer, L., Mori, Y., Nishida, M.

    FASEB Journal   33 ( 9 )   9785 - 9796   2019.09( ISSN:0892-6638

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Vascular smooth muscle cells (VSMCs) play critical roles in the stability and tonic regulation of vascular homeostasis. VSMCs can switch back and forth between highly proliferative synthetic and fully differentiated contractile phenotypes in response to changes in the vessel environment. Although abnormal phenotypic switching of VSMCs is a hallmark of vascular disorders such as atherosclerosis and restenosis after angioplasty, how control of VSMC phenotypic switching is dysregulated in pathologic conditions remains obscure. We found that inhibition of canonical transient receptor potential 6 (TRPC6) channels facilitated contractile differentiation of VSMCs through plasma membrane hyperpolarization. TRPC6-deficient VSMCs exhibited more polarized resting membrane potentials and higher protein kinase B (Akt) activity than wild-type VSMCs in response to TGF-β1 stimulation. Ischemic stress elicited by oxygen-glucose deprivation suppressed TGF-β1-induced hyperpolarization and VSMC differentiation, but this effect was abolished by TRPC6 deletion. TRPC6-mediated Ca2+ influx and depolarization coordinately promoted the interaction of TRPC6 with lipid phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of Akt activation. Given the marked up-regulation of TRPC6 observed in vascular disorders, our findings suggest that attenuation of TRPC6 channel activity in pathologic VSMCs could be a rational strategy to maintain vascular quality control by fine-tuning of VSMC phenotypic switching.-Numaga-Tomita, T., Shimauchi, T., Oda, S., Tanaka, T., Nishiyama, K., Nishimura, A., Birnbaumer, L., Mori, Y., Nishida, M. TRPC6 regulates phenotypic switching of vascular smooth muscle cells through plasma membrane potential-dependent coupling with PTEN.

    DOI: 10.1096/fj.201802811R

    PubMed

  • Ibudilast attenuates doxorubicin-induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes Reviewed

    Nishiyama, K., Numaga-Tomita, T., Fujimoto, Y., Tanaka, T., Toyama, C., Nishimura, A., Yamashita, T., Matsunaga, N., Koyanagi, S., Azuma, Y.-T., Ibuki, Y., Uchida, K., Ohdo, S., Nishida, M.

    British Journal of Pharmacology   176 ( 18 )   3723 - 3738   2019.09( ISSN:0007-1188

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    BACKGROUND AND PURPOSE: Doxorubicin is a highly effective anticancer agent but eventually induces cardiotoxicity associated with increased production of ROS. We previously reported that a pathological protein interaction between TRPC3 channels and NADPH oxidase 2 (Nox2) contributed to doxorubicin-induced cardiac atrophy in mice. Here we have investigated the effects of ibudilast, a drug already approved for clinical use and known to block doxorubicin-induced cytotoxicity, on the TRPC3-Nox2 complex. We specifically sought evidence that this drug attenuated doxorubicin-induced systemic tissue wasting in mice. EXPERIMENTAL APPROACH: We used the RAW264.7 macrophage cell line to screen 1,271 clinically approved chemical compounds, evaluating functional interactions between TRPC3 channels and Nox2, by measuring Nox2 protein stability and ROS production, with and without exposure to doxorubicin. In male C57BL/6 mice, samples of cardiac and gastrocnemius muscle were taken and analysed with morphometric, immunohistochemical, RT-PCR and western blot methods. In the passive smoking model, cells were exposed to DMEM containing cigarette sidestream smoke. KEY RESULTS: Ibudilast, an anti-asthmatic drug, attenuated ROS-mediated muscle toxicity induced by doxorubicin treatment or passive smoking, by inhibiting the functional interactions between TRPC3 channels and Nox2, without reducing TRPC3 channel activity. CONCLUSIONS AND IMPLICATIONS: These results indicate a common mechanism underlying induction of systemic tissue wasting by doxorubicin. They also suggest that ibudilast could be repurposed to prevent muscle toxicity caused by anticancer drugs or passive smoking.

    DOI: 10.1111/bph.14777

    PubMed

  • TRPC3-Nox2 axis mediates nutritional deficiency-induced cardiomyocyte atrophy Reviewed

    Sudi, S.B., Tanaka, T., Oda, S., Nishiyama, K., Nishimura, A., Sunggip, C., Mangmool, S., Numaga-Tomita, T., Nishida, M.

    Scientific Reports   9 ( 1 )   9785 - 9785   2019.07

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Myocardial atrophy, characterized by the decreases in size and contractility of cardiomyocytes, is caused by severe malnutrition and/or mechanical unloading. Extracellular adenosine 5'-triphosphate (ATP), known as a danger signal, is recognized to negatively regulate cell volume. However, it is obscure whether extracellular ATP contributes to cardiomyocyte atrophy. Here, we report that ATP induces atrophy of neonatal rat cardiomyocytes (NRCMs) without cell death through P2Y2 receptors. ATP led to overproduction of reactive oxygen species (ROS) through increased amount of NADPH oxidase (Nox) 2 proteins, due to increased physical interaction between Nox2 and canonical transient receptor potential 3 (TRPC3). This ATP-mediated formation of TRPC3-Nox2 complex was also pathophysiologically involved in nutritional deficiency-induced NRCM atrophy. Strikingly, knockdown of either TRPC3 or Nox2 suppressed nutritional deficiency-induced ATP release, as well as ROS production and NRCM atrophy. Taken together, we propose that TRPC3-Nox2 axis, activated by extracellular ATP, is the key component that mediates nutritional deficiency-induced cardiomyocyte atrophy.

    DOI: 10.1038/s41598-019-46252-2

    PubMed

  • Depolysulfidation of Drp1 induced by low-dose methylmercury exposure increases cardiac vulnerability to hemodynamic overload Reviewed

    Nishimura, A., Shimoda, K., Tanaka, T., Toyama, T., Nishiyama, K., Shinkai, Y., Numaga-Tomita, T., Yamazaki, D., Kanda, Y., Akaike, T., Kumagai, Y., Nishida, M.

    Science Signaling   12 ( 587 )   2019.06( ISSN:1945-0877

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Chronic exposure to methylmercury (MeHg), an environmental electrophilic pollutant, reportedly increases the risk of human cardiac events. We report that exposure to a low, non-neurotoxic dose of MeHg precipitated heart failure induced by pressure overload in mice. Exposure to MeHg at 10 ppm did not induce weight loss typical of higher doses but caused mitochondrial hyperfission in myocardium through the activation of Drp1 by its guanine nucleotide exchange factor filamin-A. Treatment of neonatal rat cardiomyocytes with cilnidipine, an inhibitor of the interaction between Drp1 and filamin-A, suppressed mitochondrial hyperfission caused by low-dose MeHg exposure. Modification of cysteine residues in proteins with polysulfides is important for redox signaling and mitochondrial homeostasis in mammalian cells. We found that MeHg targeted rat Drp1 at Cys624, a redox-sensitive residue whose SH side chain forms a bulky and nucleophilic polysulfide (Cys624-S(n)H). MeHg exposure induced the depolysulfidation of Cys624-S(n)H in Drp1, which led to filamin-dependent activation of Drp1 and mitochondrial hyperfission. Treatment with NaHS, which acts as a donor for reactive polysulfides, reversed MeHg-evoked Drp1 depolysulfidation and vulnerability to mechanical load in rodent and human cardiomyocytes and mouse hearts. These results suggest that depolysulfidation of Drp1 at Cys624-S(n)H by low-dose MeHg increases cardiac fragility to mechanical load through filamin-dependent mitochondrial hyperfission.

    DOI: 10.1126/scisignal.aaw1920

    PubMed

  • Correlation between toll-like receptor 4 and nucleotide-binding oligomerization domain 2 (NOD2) and pathological severity in dogs with chronic gastrointestinal diseases Reviewed

    Aono, K., Azuma, Y.-T., Nabetani, T., Hatoya, S., Furuya, M., Miki, M., Hirota, K., Fujimoto, Y., Nishiyama, K., Ogata, Y., Mochizuki, T., Tani, H.

    Veterinary Immunology and Immunopathology   210   15 - 22   2019.04( ISSN:0165-2427

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Toll-like receptor 4 (TLR4), nucleotide-binding oligomerization domain 2 (NOD2), and TNF-α play important roles in human inflammatory bowel diseases. The aim of this study was to elucidate the relationship between Toll-like receptor 4, NOD2, and TNF-α and the severity of chronic gastrointestinal diseases in dogs. We examined the expression levels of TLR4, NOD2, and TNF-α in the stomach, duodenum, ileum, colon, and rectum obtained from 21 dogs with chronic gastrointestinal disease, including inflammatory bowel disease, high-grade lymphoma, food responsive enteropathy, chronic pancreatitis, low-grade lymphoma, inflammatory colorectal polyp, and chronic colitis. Next, we demonstrated whether there is good correlation between the expression levels of TLR4, NOD2, and TNF-α and the histopathological analysis of each sample. We found that the level of TLR4 expression in the ileum of dogs with chronic gastrointestinal disease was positively associated with the histopathological severity. We also found that the level of NOD2 expression in the duodenum, stomach, and rectum was positively associated with the histopathological severity. However, there was no correlation between TNF-α expression in the 5 regions tested in this study and the histopathological severity. These findings indicate that TLR4 and NOD2 are remarkably associated with the severity of chronic gastrointestinal disease in dogs.

    DOI: 10.1016/j.vetimm.2019.03.003

    PubMed

  • Chronic kidney disease after 5/6 nephrectomy disturbs the intestinal microbiota and alters intestinal motility Reviewed

    Nishiyama, K., Aono, K., Fujimoto, Y., Kuwamura, M., Okada, T., Tokumoto, H., Izawa, T., Okano, R., Nakajima, H., Takeuchi, T., Azuma, Y.-T.

    Journal of Cellular Physiology   234 ( 5 )   6667 - 6678   2019.04( ISSN:0021-9541

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Organ-organ crosstalk is involved in homeostasis. Gastrointestinal symptoms are common in patients with renal failure. The aim of this study was to elucidate the relationship between gastrointestinal motility and gastrointestinal symptoms in chronic kidney disease. We performed studies in C57BL/6 mice with chronic kidney disease after 5/6 nephrectomy. Gastrointestinal motility was evaluated by assessing the ex vivo responses of ileum and distal colon strips to electrical field stimulation. Feces were collected from mice, and the composition of the gut microbiota was analyzed using 16S ribosomal RNA sequencing. Mice with chronic kidney disease after 5/6 nephrectomy showed a decreased amount of stool, and this constipation was correlated with a suppressed contraction response in ileum motility and decreased relaxation response in distal colon motility. Spermine, one of the uremic toxins, inhibited the contraction response in ileum motility, but four types of uremic toxins showed no effect on the relaxation response in distal colon motility. The 5/6 nephrectomy procedure disturbed the balance of the gut microbiota in the mice. The motility dysregulation and constipation were resolved by antibiotic treatments. The expression levels of interleukin 6, tumor necrosis factor-α, and iNOS in 5/6 nephrectomy mice were increased in the distal colon but not in the ileum. In addition, macrophage infiltration in 5/6 nephrectomy mice was increased in the distal colon but not in the ileum. We found that 5/6 nephrectomy altered gastrointestinal motility and caused constipation by changing the gut microbiota and causing colonic inflammation. These findings indicate that renal failure was remarkably associated with gastrointestinal dysregulation.

    DOI: 10.1002/jcp.27408

    PubMed

  • TRPC channels in exercise-mimetic therapy Reviewed

    Numaga-Tomita, T., Oda, S., Nishiyama, K., Tanaka, T., Nishimura, A., Nishida, M.

    Pflugers Archiv European Journal of Physiology   471 ( 3 )   507 - 517   2019.03( ISSN:0031-6768

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    Publishing type:Research paper (scientific journal)   International / domestic magazine:International journal  

    Physical exercise yields beneficial effects on all types of muscle cells, which are essential for the maintenance of cardiovascular homeostasis and good blood circulation. Daily moderate exercise increases systemic antioxidative capacity, which can lead to the prevention of the onset and progression of oxidative stress-related diseases. Therefore, exercise is now widely accepted as one of the best therapeutic strategies for the treatment of ischemic (hypoxic) diseases. Canonical transient receptor potential (TRPC) proteins are non-selective cation channels activated by mechanical stress and/or stimulation of phospholipase C-coupled surface receptors. TRPC channels, especially diacylglycerol-activated TRPC channels (TRPC3 and TRPC6; TRPC3/6), play a key role in the development of cardiovascular remodeling. We have recently found that physical interaction between TRPC3 and NADPH oxidase (Nox) 2 under hypoxic stress promotes Nox2-dependent reactive oxygen species (ROS) production and mediates rodent cardiac plasticity, and inhibition of the TRPC3-Nox2 protein complex results in enhancement of myocardial compliance and flexibility similar to that observed in exercise-treated hearts. In this review, we describe current understanding of the roles of TRPC channels in striated muscle (patho)physiology and propose that targeting TRPC-based protein complexes could be a new strategy to imitate exercise therapy.

    DOI: 10.1007/s00424-018-2211-3

    PubMed

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MISC

  • 【コバレント創薬の新たな可能性】Gタンパク質共役型受容体を標的としたコバレント創薬

    近藤 萌, 西山 和宏, 西村 明幸, 加藤 百合, 西田 基宏

    日本薬理学雑誌   157 ( 5 )   356 - 360   2022.09( ISSN:0015-5691

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    Gタンパク質共役型受容体(GPCRs)は,細胞内環境の変化(物理化学的刺激)を細胞内情報に変換し,伝達する上で極めて重要な役割を果たしている.リガンド刺激後,多くのGPCRはリン酸化され,β-アレスチン依存性の内在化によって再利用または分解される.このプロセスは,GPCRタンパク質の品質管理を維持するための重要な機構である.一方で,β-アレスチン感受性の低いGPCRがどのように品質管理されるかは不明であった.我々は,β-アレスチン低感受性のプリン作動性P2Y6受容体(P2Y6R)に着目し,リン酸化に依存しないGPCR内在化経路(Redox-dependent Alternative Internalization:REDAI)の存在を新たに見出した.P2Y6Rはマクロファージに高発現しており,大腸炎の発症・進展に深くかかわっている.我々は,食品中に含まれる親電子物質がP2Y6RのREDAIを誘導し,抗炎症効果をもたらす一方で,REDAIの抑制が大腸炎の悪化をもたらすことをマウスで実証した.これらの結果は,GPCRのREDAIを標的にする創薬が,炎症性疾患の画期的な治療戦略となることを強く示唆している.(著者抄録)

  • 【新興ウイルス感染症の早期予防・治療を目指して〜COVID-19対策から考える〜】COVID-19治療薬開発を目指したエコファーマ研究

    加藤 百合, 西山 和宏, 西村 明幸, 西田 基宏

    日本薬理学雑誌   157 ( 2 )   119 - 123   2022.03( ISSN:0015-5691

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    新型コロナウイルス感染症(COVID-19)は,2019年に中国・武漢で発症が確認されて以来,全世界で猛威を奮っている新興感染症である.有効な治療法は未だ確立されておらず,COVID-19重症化機構の解明,予防・治療法の確立が急務となっている.主な感染経路として,新型コロナウイルス(SARS-CoV-2)表面にあるspikeタンパク質(Sタンパク質)が宿主細胞膜上のSARS-CoV-2ウイルスの認識受容体angiotensin converting enzyme(ACE)2タンパク質と結合し,エンドサイトーシスを介して細胞内に侵入する.COVID-19は肺への重篤な障害が報告されているが,ACE2は肺だけではなく心臓や消化器など様々な組織に発現しているため,細胞間のウイルス感染拡大,つまり感染重症化は肺だけではなく全身の組織でも起こりうる.我々は,COVID-19重症化リスクを増加させる既往症に心疾患が含まれることや,COVID-19後遺症にも心機能障害が含まれることから,心臓でのSARS-CoV-2感染・重症化の機構に着目した.その結果,心臓のACE2受容体がCOVID-19重症化リスク因子と示唆されている様々な環境ストレス曝露によって増加すること,その分子機構として,心筋リモデリングを制御する膜タンパク質複合体(TRPC3-Nox2)形成が関与することを新たに見いだした.さらに,TRPC3-Nox2タンパク質複合体形成を阻害する既承認薬の中から,Sタンパク質曝露によるACE2内在化を抑制する化合物クロミプラミン(三環系抗うつ薬)を同定した.本稿では,心臓におけるTRPC3-Nox2複合体形成を介したACE2受容体の発現制御機構,および人工組換え三量体Sタンパク質を用いたinvitroスクリーニング(偽感染モデル)とその結果について紹介する.(著者抄録)

  • Cardiac robustness regulated by reactive sulfur species(和訳中)

    Nishimura Akiyuki, Tanaka Tomohiro, Kato Yuri, Nishiyama Kazuhiro, Nishida Motohiro

    Journal of Clinical Biochemistry and Nutrition   70 ( 1 )   1 - 6   2022.01( ISSN:0912-0009

  • 【生命を支える超硫黄分子の代謝と革新的な計測技術】心筋の頑健性と超硫黄分子代謝

    西田 基宏, 西村 明幸, 田中 智弘, 加藤 百合, 西山 和宏

    生化学   93 ( 5 )   702 - 707   2021.10( ISSN:0037-1017

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    心筋は,動物が生まれてから死ぬまで入れ替わることなく,常に拍動し続けるきわめて頑健な細胞である.最近の研究から,システインパースルフィド(CysSSH)やポリスルフィド(CysSnH)に代表される硫黄原子が複数連なった,電子授受能に優れた分子種(超硫黄分子)が,ミトコンドリアの形態機能維持を介して心筋のストレス抵抗力に寄与することが明らかになってきた.本稿では,超硫黄分子によるミトコンドリアのエネルギー代謝や品質管理維持の分子制御機構および心臓におけるその病態生理学的意義について,筆者らの最新の知見を紹介する.(著者抄録)

  • 先端的医薬品開発を目指す薬理学・臨床薬理学研究 筋萎縮性疾患治療薬を指向したエコファーマ研究

    西田 基宏, 西山 和宏, 加藤 百合, 小谷 さゆみ, 田中 智弘, 西村 明幸

    臨床薬理   52 ( 2 )   39 - 42   2021.03( ISSN:0388-1601

  • 【食と健康を結ぶメディカルサイエンス 生体防御系を亢進し、健康の維持に働く分子機構】(第3章)食による受容体を介した細胞機能活性化 細胞膜受容体 Gタンパク質共役型受容体

    西田 基宏, 西山 和宏, 加藤 百合, 田中 智弘, 西村 明幸

    実験医学   38 ( 10 )   1714 - 1718   2020.06( ISSN:0288-5514

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    Gタンパク質共役型受容体(GPCR)は、細胞外の環境変化に伴う物理化学的刺激を認識し、細胞内に適応するための情報を伝達する'センサー'タンパク質の1つである。GPCRは薬の最有力標的分子として世界中で研究され続けられているものの、われわれが普段から口にする食事がGPCRに及ぼす影響については、いまだ十分には解き明かされていない。本稿では、機能性食品成分によるGPCRのアティピカルな機能修飾から、食が自然治癒力を高める分子機構を読み解く。(著者抄録)

  • 【臨床医が知っていてほしい循環器基礎研究最新の成果】心不全 ミトコンドリア異常は心不全の原因か

    西田 基宏, 加藤 百合, 田中 智弘, 西山 和宏, 西村 明幸

    循環器内科   87 ( 5 )   579 - 584   2020.05( ISSN:1884-2909

  • Is mitochondrial abnormality the cause of heart failure?

    87 ( 5 )   579 - 584   2020.05( ISSN:1884-2909

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  • がんから学ぶ心脈管学 抗がん剤投与による心筋萎縮におけるTRPC3-Nox2複合体形成の役割

    西田 基宏, 田中 智弘, 小田 紗矢香, 西村 明幸, 西山 和宏

    血管   43 ( 1 )   25 - 25   2020.01( ISSN:0911-4637

  • 【酸化ストレスと組織の恒常性維持】酸化/還元ストレスと心臓

    西田 基宏, 西山 和宏, 田中 智弘, 西村 明幸

    臨床免疫・アレルギー科   72 ( 1 )   29 - 35   2019.07( ISSN:1881-1930

  • シルニジピンによるミトコンドリア品質維持機構と難治性疾患への適応拡大

    西田 基宏, 西村 明幸, 田中 智弘, 下田 翔, 西山 和宏, 井手 友美

    臨床薬理の進歩   ( 40 )   45 - 53   2019.06( ISSN:0914-4366

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    シルニジピンが心筋梗塞(MI)後のミトコンドリア過分裂を抑制する分子機構の解明と、シルニジピンの難治性疾患への適応拡大の可能性の検証を目的とした。MIモデルマウスにおいて、Drp1をノックダウンさせることでほぼ完全に早期老化誘導が抑制されたことから、Drp1を介するミトコンドリア過剰分裂が心筋早期老化を仲介することが示唆された。そこでDrp1阻害活性を持つ既承認薬のスクリーニングを行ったところ、高血圧治療薬として使われるジヒドロピリジン(DHP)系Ca2+拮抗薬の一つであるシルニジピンがミトコンドリア分裂を顕著に抑制することを見出した。シルニジピンは、Ca2+チャネル阻害やDrp1直接阻害とは異なる機構が関与していると考えられ、低酸素ストレス依存的にDrp1と結合するタンパク質を網羅的に調べた結果、アクチン結合タンパク質であるフィラミンA(FLNa)が同定された。検討の結果、FLNaはDrp1の病態特異的なGEFとして働くこと、およびシルニジピンは低酸素(虚血)依存的に生じるDrp1-FLNa相互作用を抑制することで、ミトコンドリア過分裂を伴う心不全進行を抑制する可能性が示された。また、シルニジピンが慢性心不全の予後改善だけでなく、ミトコンドリア機能異常を伴う難治性疾患(筋萎縮性側索硬化症や炎症性腸疾患)の予後改善にも貢献しうることを動物レベルで実証した。シルニジピンが心血管病リスク要因である高血糖を顕著に改善させる作用を持つことも高血圧患者カルテデータの後ろ向き解析から明らかにした。

  • シルニジピンの難治性疾患へのドラッグリポジショニング

    西山 和宏, 田丸 愛, 西村 明幸

    ファルマシア   55 ( 3 )   228 - 232   2019( ISSN:0014-8601

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    シルニジピンはジヒドロピリジン系カルシウム拮抗薬のひとつで現在,高血圧症治療薬として使用されている.最近,我々のグループはシルニジピンが過剰なミトコンドリア分裂とそれに伴う心筋老化を抑制し、心筋梗塞後の慢性心不全を改善することを明らかとした.本稿では,シルニジピンの新たな作用を解説しながら,ミトコンドリア品質管理を標的としたシルニジピンの難治性疾患へのドラッグ・リポジショニングの可能性を紹介したい.

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