Cardiac Neprilysin Plays an Important Role in Hypertensive Cardiac Remodeling

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15898
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Nara Medical University
• Principal Investigator: Nakagawa Hitoshi 奈良県立医科大学, 医学部附属病院, 助教 (20533730)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ネプリライシン / ナトリウム利尿ペプチド

Outline of Final Research Achievements

NEP (Neprilysin) degrades natriuretic peptides, and its inhibition is a clinically accepted target for heart failure treatment. To study the local function of NEP in the heart, we generated transgenic mice overexpressing NEP, specifically in cardiomyocytes (CM-NEP Tg).Transverse aortic constriction (TAC) surgery significantly induced cardiac hypertrophy and interstitial fibrosis in CM-NEP Tg mice as compared with wild type mice. TAC CM-NEP Tg, but not TAC WT, mice developed cardiac dysfunction secondary to TAC with echocardiography. Furthermore, administration of human ANP to raise plasma ANP levels comparable to those in WT mice neither improved the exacerbated cardiac hypertrophy and fibrosis nor recovered impaired cardiac function in CM-NEP Tg mice after TAC. In conclusion, overexpression of NEP in cardiomyocytes promoted degradation of natriuretic peptides in the heart and led to an exaggerated response of hypertrophy and fibrosis to pressure overload.

Free Research Field

心不全

Academic Significance and Societal Importance of the Research Achievements

心臓組織におけるネプリライシンの発現は心臓組織のcGMPを低下させ，大動脈縮窄術後の心肥大，心臓間質の線維化，心機能の低下を引き起こした．心臓組織でのナトリウム利尿ペプチドに対するネプリライシンの局所的な働きが，心臓リモデリングに重要であると思われる。このことは、ネプリライシンを阻害する治療薬が、心臓の収縮能を改善することを示唆しており治療薬としての新たな意義を提唱するものである。