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Am J Physiol Heart Circ Physiol. 2018 Jun 29. doi: 10.1152/ajpheart.00595.2017. [Epub ahead of print]

Inhibition of Programmed Necrosis Limits Infarct Size through Altered Mitochondrial and Immune Responses in the Aged Female Rat Heart.

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Physiology, The Pennsylvania State University.
Pennsylvania State University.
Physiology and Kinesiology, The Pennsylvania State University, United States.


Both advancing age and estrogen loss exacerbate acute myocardial infarction (AMI) in the female heart. However, the mechanistic underpinnings of age-related differences in cell death following ischemia/reperfusion (I/R) injury in females and reductions in cardioprotective reserve capacity remains largely unexplored. The aim of this study was to determine the efficacy of programmed necrosis inhibition on infarct size reduction and preservation of LV function following I/R injury with female aging. F344 rats were ovariectomized (OVX) at 15 mo and studied at 24 mo (MO OVX) vs adult ovary-intact (6 mo). Following in vivo coronary artery ligation (CAL; 55 min I and 2 or 6 hr R), Necrostatin-1 (nec-1; 3.5 mg/kg or 5.7 mg/kg) delivered upon R, significantly reduced infarct size by 37% and improved LV function in MO OVX (p<0.01). While age-associated elevations in cyclophilin D and mitochondrial acetylation (p<0.001) were unaffected by nec-1, profound reductions in IL-1, IL-6, TNF╬▒ (p<0.05) and cardiac immune cell infiltration were observed in MO OVX but not adult. We conclude that chronic inflammation and postmenopausal estrogen-deficiency conspire to exacerbate AMI through a mechanism involving exaggerated mitochondrial-mediated programmed necrosis through receptor interacting protein 1 (RIP1) signaling. Modulatory effects of PN inhibition on proinflammatory cytokine production following I/R reveal a potentially important mechanistic target to restore and preserve cardiac function in the ovariectomized aged female heart.


aging; ischemic heart; mitochondria; programmed necrosis

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