| First Author | Zou R | Year | 2024 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1870 |
| Issue | 2 | Pages | 166958 |
| PubMed ID | 37963542 | Mgi Jnum | J:344308 |
| Mgi Id | MGI:7572192 | Doi | 10.1016/j.bbadis.2023.166958 |
| Citation | Zou R, et al. (2024) Cardiomyocyte-specific deletion of endothelin receptor A (ET(A)) obliterates cardiac aging through regulation of mitophagy and ferroptosis. Biochim Biophys Acta Mol Basis Dis 1870(2):166958 |
| abstractText | 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 ET(A) receptor knockout (ET(A)KO) 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 Fe(2+), 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 Ca(2+) mishandling (dampened intracellular Ca(2+) release and prolonged decay), the effects with the exception of plasma AngII, ET-1 and Fe(2+) were mitigated by ET(A)KO. Advanced age facilitated O(2)(-) 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 Ca(2+) proteins (SERCA2a and phospholamban), the effects of which were reversed by ET(A) ablation. ET-1 provoked ferroptosis in vitro, the response was nullified by the ET(A) receptor antagonist BQ123 and mitophagy inducer CsA. ET(A) but not ET(B) receptor antagonism reconciled cardiac aging, which was abrogated by inhibition of mitophagy and ferroptosis. These findings collectively denote promises of targeting ET(A), mitophagy and ferroptosis in the management of aging-associated cardiac remodeling and contractile defect. |
