Therapeutic application of PKG-1alpha redox modulation and the disparate cGMP regulation in heart failure

2020 Fiscal Year Final Research Report

• Project/Area Number: 17K09583
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kumamoto University
• Principal Investigator: Nakamura Taishi 熊本大学, 病院, 准教授 (60582947)
• Co-Investigator(Kenkyū-buntansha): 泉家 康宏 熊本大学, 病院, 非常勤診療医師 (10515414)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: プロテインキナーゼG / 心不全 / システインレドックス / サイクリックGMPシグナルの層別化 / 病的心肥大

Outline of Final Research Achievements

Intracellular cGMP and the main effector PKG1α prevent pathological hypertrophy and heart failure. PKG is principally activated by cGMP binding to the regulatory site, but it can be stimulated with oxidation at C42 where is located near N-terminal dimerization domain. We found the redox modulation controls subcellular localization and protein-protein interaction to the substrates, independently of kinase activity. C42 oxidation resulted in enhancing colocalization with PDE5 and thus phosphorylate S92, which explains PDE5 inhibitor is responsive as the disease severity goes worse. Moreover, we found anew phosphorylation site in tuberin (TSC2) which negatively regulates the downstream mTORC1 signaling and thereby leads to suppress maladaptive hypertrophy. We also uncovered the phosphorylation site at TSC2 can be hampered by C42 oxidation. Our research works successfully contribute to provide a new concept into heart failure therapy leveraging cGMP/PKG signaling.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

細胞内サイクリックGMPとプロテインキナーゼ(PKG1α)の活性化は、超高齢社会で蔓延する心不全の治療標的として期待されている。本研究は、活性レベルとは独立し、PKG1αの機能を制御することがわかってきた特異的なシステインレドックス調節機構に焦点をあてた研究であり、C42酸化による細胞内局在化と基質相互作用変化の分子機序の解明により、その標的有用性と治療応用としての発展性を示すトランスレーショナルな臨床的意義の高い研究である。