Sex-dependent myocardial necrosis-like signaling in rats with heart failure due to chronic pressure overload.

Abstract

Sex profoundly influences cardiac adaptation to stressful stimuli; however, sex-specific mechanisms underlying heart failure (HF) due to necrosis-like cell death remain unclear. Using a neonatal rat model of abdominal aortic constriction, which mimics pressure overload-induced HF, we investigated cardiac function and morphology and provided a comprehensive molecular analysis of cell death pathways. Although necroptosis was evident in failing hearts of both sexes, albeit with more excessive remodeling in males, pyroptosis and ferroptosis were not prominent. At the cellular level, macrophages likely underlie this damage via different mechanisms in each sex. In females, the upstream activators of necroptosis indicated a proinflammatory environment, with a role of tumor necrosis factor-mediated canonical pathway involving receptor-interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like pseudokinase. Conversely, in males, RIP3 activation was linked to an altered redox status and increased mitochondrial DNA oxidation. These sex-divergent pronecroptotic events underscore the necessity for personalized therapeutic strategies targeting distinct cell-damaging molecular pathways to improve HF outcomes.This study identifies necroptosis as a key pathomechanism in pressure overload-induced heart failure, with sex-dependent, prodeath molecular events. Novel findings indicate distinct pronecroptotic triggers: in males, necroptosis is driven by oxidative stress and mitochondrial DNA damage, whereas in females, a proinflammatory pathway involving tumor necrosis factor and compensatory mitochondrial biogenesis predominates. Pyroptosis and ferroptosis do not appear to be prominent. These sex-specific molecular necrosis-like divergences are important for developing personalized therapeutic strategies for heart failure.