In a rat model of pressure overload-induced heart failure, necroptosis was driven by TNF-mediated pathways in females and altered redox status with mitochondrial DNA oxidation in males.
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. While 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 pro-inflammatory 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 (MLKL). Conversely, in males, RIP3 activation was linked to an altered redox status and increased mitochondrial DNA oxidation. These sex-divergent pro-necroptotic events underscore the necessity for personalized therapeutic strategies targeting distinct cell-damaging molecular pathways to improve HF outcomes.
Horváth et al. (Thu,) conducted a other in Heart failure due to chronic pressure overload. Abdominal aortic constriction was evaluated on Cardiac function, morphology, and molecular analysis of cell death pathways. In a rat model of pressure overload-induced heart failure, necroptosis was driven by TNF-mediated pathways in females and altered redox status with mitochondrial DNA oxidation in males.