Aging‐Related Myocardial Susceptibility Lowers Cardiac Tolerance to Chronic Intermittent Hypoxia Through Dynamin‐Related Protein 1‐Associated Mitochondrial Vulnerability

Vollständiger Abstract

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ABSTRACT Chronic intermittent hypoxia (CIH), a cardinal pathophysiological feature of obstructive sleep apnea (OSA), repeatedly exposes the heart to hypoxia‐reoxygenation stress. The cardiac outcome of CIH, however, may depend on the biological state of the target myocardium. Here, we investigated whether a pre‐existing aging‐related myocardial susceptibility lowers the tolerance threshold for CIH‐induced injury and whether Dynamin‐related protein 1 (Drp1) contributes to the enhanced vulnerability of senescence‐like cardiomyocytes under CIH. Using G3 Tert‐deficient (Tert −/− ) mice and D‐galactose (D‐gal)‐induced senescence‐like primary cardiomyocytes, we show that aging‐related susceptibility consistently amplifies CIH‐induced cardiac injury. In young wild‐type mice, 8 weeks CIH induced early cardiac remodeling and senescence‐associated myocardial stress without overt systolic decompensation. In Tert −/− mice, the same CIH exposure shifted the cardiac response further toward maladaptive remodeling. Compared with CIH alone, EF and FS were reduced by an additional 24.6% and 15.8%, respectively. In senescence‐like cardiomyocytes, CIH amplified mitochondrial vulnerability, with impaired energy production, elevated mitochondrial oxidative stress, and a fission‐biased mitochondrial dynamics marker profile. Drp1 knockdown did not fully reverse this mitochondrial state but restored 55.1% of the CIH + D‐gal induced ATP decline and reversed 47.4% of the mitochondrial ROS excess, while attenuating DNA damage response activation and senescence‐associated signaling. These findings indicate that aging‐related myocardial susceptibility is not a passive contextual factor in CIH‐induced injury but a biological state that actively shapes the cardiac response to repeated hypoxia‐reoxygenation stress. Drp1‐associated mitochondrial dynamics imbalance may represent a functional link between diminished mitochondrial stress tolerance and amplified cardiomyocyte vulnerability.