Altered mitochondrial respiration, morphology, and quality control collectively contribute to mitochondrial dysfunction in the aged heart. Because myocardial infarction remains the leading cause of death in aged women, the present study utilized a novel rodent model to recapitulate human menopause to interrogate the combination of age and estrogen deficiency on mitochondrial ultrastructure and function with cardiac ischemia/reperfusion (I/R) injury. Female F344 rats were ovariectomized (OVX) at 15 months and studied at 24 months (MO OVX; n = 40) vs adult ovary intact (6 months; n = 41). Temporal declines in estrogen concomitant with increased visceral adipose tissue were observed in MO OVX vs adult. Following in vivo coronary artery ligation or sham surgery, state 3 mitochondrial respiration was selectively reduced by age in subsarcolemmal mitochondria (SSM) and by I/R in interfibrillar mitochondria (IFM); left ventricular maximum dP/dt was reduced in MO OVX (p < 0.05). Elevated cyclophilin D and exacerbated I/R-induced mitochondrial acetylation in MO OVX suggest permeability transition pore involvement and reduced protection vs adult (p < 0.05). Mitochondrial morphology by TEM revealed an altered time course of autophagy coordinate with attenuated Drp1 and LC3BII protein levels with age-associated estrogen loss (p < 0.05). Here, reductions in both SSM and IFM function may play an additive role in enhanced susceptibility to regional I/R injury in aged estrogen-deficient female hearts. Moreover, novel insight into altered cardiac mitochondrial quality control garnered here begins to unravel the potentially important regulatory role of mitochondrial dynamics on sustaining respiratory function in the aged female heart.

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, TNFα (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.

Hutchinson,~ who invented the spirometer (1846), determined the vital capacity in twenty-two cases of early and nine cases of advanced pulmonary tuberculosis, and found that the vital capacity was subnormal in all. In the former group he found a decrease of from 10 to 50 per cent, in the latter of from 40 to 80 per cent. He calculated the normal figures from the height of the patient. 2 Since then numerous

Transient ACE (angiotensin-converting enzyme) inhibition in spontaneously hypertensive rats is known to protect against future injury-induced cardiac inflammation, fibrosis, and dysfunction; however, the mechanisms of protection have not been delineated. Here, we used single-cell RNA sequencing to test the hypothesis that transient ACE inhibitor treatment would induce a persistent shift in cardiac fibroblast subpopulations. Adult male spontaneously hypertensive rats (11 weeks old, hypertensive with cardiac hypertrophy) were treated for 2 weeks with an ACE inhibitor, enalapril (30 mg/kg per day, PO), or water (untreated spontaneously hypertensive rats) followed by a 2-week washout period (n=7/group). Cardiac fibroblasts were isolated from the left ventricle and subjected to single-cell RNA sequencing. Nine clusters of fibroblasts were identified, with 98% of cells in clusters 0 to 6. The transient treatment produced significant changes both within and across clusters. Cluster 1 depicted a highly fibrogenic gene profile, with cluster 6 serving as a gateway to cluster 1. Transient ACE inhibition depleted the gateway and expanded cluster 0, which was the least fibrogenic profile. Moreover, within cluster 1 fibroblasts, ACE inhibition reduced expression of individual fibrosis genes (eg, COL1A1, COL3A1, and FN1 ; all P <1×10 -35 ). Clusters 2 to 5 reflected proliferative, moderately fibrogenic, translationally active, and less inflammatory subsets of fibroblasts, all of which exhibited attenuated fibrogenic gene expression after transient ACE inhibition. In conclusion, transient ACE inhibition shifts cardiac fibroblast subpopulations and degree of activation resulting in an overall reduced fibrogenic phenotype.

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