Cardiomyocyte-specific deletion of endothelin receptor A (ETA) obliterates cardiac aging through regulation of mitophagy and ferroptosis

粒体自噬 内科学 内分泌学 生物 内皮素1 自噬 磷化氢 内皮素受体 受体 医学 心力衰竭 细胞凋亡 生物化学
作者
Rongjun Zou,Wanting Shi,Aslı F. Ceylan,Maolong Dong,Miao Zhang,Zengxiao Zou,Bo Peng,Feng Dong,Subat Turdi,Jie Lin,Yingmei Zhang,Ge Wang,Xiaoping Fan,Jun Ren
出处
期刊:Biochimica Et Biophysica Acta: Molecular Basis Of Disease [Elsevier]
卷期号:1870 (2): 166958-166958 被引量:4
标识
DOI:10.1016/j.bbadis.2023.166958
摘要

Advanced aging evokes unfavorable changes in the heart including cardiac remodeling and contractile dysfunction although the underlying mechanism remains elusive. This study was conducted to evaluate the role of endothelin-1 (ET-1) in the pathogenesis of cardiac aging and mechanism involved. Echocardiographic and cardiomyocyte mechanical properties were determined in young (5–6 mo) and aged (26–28 mo) wild-type (WT) and cardiomyocyte-specific ETA receptor knockout (ETAKO) mice. GSEA enrichment identified differentially expressed genes associated with mitochondrial respiration, mitochondrial protein processing and mitochondrial depolarization in cardiac aging. Aging elevated plasma levels of ET-1, Ang II and suppressed serum Fe2+, evoked cardiac remodeling (hypertrophy and interstitial fibrosis), contractile defects (fractional shortening, ejection fraction, cardiomyocyte peak shortening, maximal velocity of shortening/relengthening and prolonged relengthening) and intracellular Ca2+ mishandling (dampened intracellular Ca2+ release and prolonged decay), the effects with the exception of plasma AngII, ET-1 and Fe2+ were mitigated by ETAKO. Advanced age facilitated O2− production, carbonyl protein damage, cardiac hypertrophy (GATA4, ANP, NFATc3), ER stress, ferroptosis, compromised autophagy (LC3B, Beclin-1, Atg7, Atg5 and p62) and mitophagy (parkin and FUNDC1), and deranged intracellular Ca2+ proteins (SERCA2a and phospholamban), the effects of which were reversed by ETA ablation. ET-1 provoked ferroptosis in vitro, the response was nullified by the ETA receptor antagonist BQ123 and mitophagy inducer CsA. ETA but not ETB receptor antagonism reconciled cardiac aging, which was abrogated by inhibition of mitophagy and ferroptosis. These findings collectively denote promises of targeting ETA, mitophagy and ferroptosis in the management of aging-associated cardiac remodeling and contractile defect.
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