New therapeutic strategies for diastolic heart failure using extracellular matrix

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06805
• 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) ; 天ヶ瀬 紀久子 立命館大学, 薬学部, 教授 (60278447)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 心線維化 / 細胞外マトリクス / NADPH oxidase

Outline of Final Research Achievements

In this experiment, we investigated the mechanism of cardiac fibrosis mediated by NOX1/NADPH oxidase (NOX1). NOX1 exacerbates cell injury induced by antitumor drugs and inhibits the production of cardiac fibroblast inhibitory factors in H9c2 cells, a rat cardiomyoblast cell line. The increased proliferation of cardiac fibroblasts induced by transforming growth factor-β or fetal bovine serum was significantly suppressed when cardiac fibroblasts were exposed to homogenates from Nox1-disrupted H9c2 cells, but not from wild-type cells. In Nox1-disrupted H9c2 cells, the expression of Podn-B, one of the splice variants of Podocan, an extracellular matrix molecule, was up-regulated. The suppressed proliferation was significantly restored when the homogenates from Podn-B-disrupted H9c2 cells were exposed to cardiac fibroblasts. In addition, cardiac diastolic dysfunction and cardiac hypertrophy were significantly improved in NOX1-deficient mice in an HFpEF model.

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。