Identification of novel therapeutic targets for cardiac fibrosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06898
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Iwata Kazumi 京都府立医科大学, 医学(系)研究科(研究院), 講師 (60305571)
• Co-Investigator(Kenkyū-buntansha): 松本 みさき 京都府立医科大学, 医学(系)研究科(研究院), 助教 (80533926)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 心線維化 / 活性酸素種 / NADPHオキシダーゼ

Outline of Final Research Achievements

We previously presented that doxorubicin-induced cardiac fibrosis was suppressed in the mice which deficient of NOX1/NADPH oxidase. We studied the role of NOX1 in the cardiac fibrosis using H9c2 cells, a rat cardiomyoblast cell line, and primary cultures of cardiac fibroblasts isolated from adult male mice. Increased proliferation of cardiac fibroblasts induced by transforming growth factor-β (10 ng/ml) or fetal bovine serum (1%) was significantly suppressed when cardiac fibroblasts were exposed to homogenates from Nox1-diurupted H9c2, but not from wild-type cells. In Nox1-disrupted H9c2 cells, expression of Collagen4a1 (Col4a), Osteoglycin (Ogn), and Podocan (Podn) were up-regulated. When the homogenates from Col4a -, Ogn -, or Podn -disrupted H9c2 were exposed to cardiac fibroblasts, suppressed proliferation was significantly restored. These findings suggest that NOX1 promotes cardiac fibrosis via down-regulation of fibrosis inhibitory factors in cardiomyocytes.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

我が国では左室駆出率の保持された心不全 (Heart Failure with Preserved Ejection Fraction: HFpEF) が心不全患者の50%以上を占めるものの、予後を改善する治療法がない現状である。HFpEFの主因は心筋細胞の肥大と線維化による拡張不全であることから、本研究ではHFpEFの新しい治療法の開発に向け、心臓の線維化を抑制する新しい分子の同定とその作用機構について検討を行った。