Work

Impaired PGC-1α-pAMPK signaling in postmenopausal women undergoing cardiac surgery and the role of nicotinamide in its reversal: Insights from a murine model

Year: 2025

Type: article

Abstract: Postmenopausal women undergoing cardiac surgery face disproportionately worse outcomes compared with men, a disparity linked to mitochondrial dysfunction following estrogen loss. We investigated sex-specific metabolic responses to cardiac stress in surgical patients and in a murine model of postmenopausal dysfunction, with a focus on proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signaling and the therapeutic potential of nicotinamide (NAM), a precursor of nicotinamide adenine dinucleotide (NAD + ). In a prospective cohort of 102 patients (51 men, 51 women) undergoing cardiac surgery with cardiopulmonary bypass, women exhibited a significantly higher incidence of diastolic dysfunction and longer hospital stays despite comparable baseline characteristics. Molecular analysis of atrial tissue revealed that men demonstrated increased postoperative PGC-1α and phosphorylated AMP-activated protein kinase (pAMPK), while women had reduced expression and also displayed a significant decline in myocardial NAD + levels. To mechanistically model these findings, ovariectomized mice on a high-fat diet exhibited reduced myocardial PGC-1α and pAMPK expression, suppressed antioxidant defenses, and increased fibrosis. NAM supplementation restored myocardial NAD + , increased PGC-1α expression, and significantly improved systolic and diastolic cardiac function. These findings indicate that loss of estrogen impairs responses to oxidative stress in postmenopausal women, predisposing to adverse outcomes after cardiac stress. NAM may represent a promising non-hormonal strategy to restore mitochondrial function and improve cardiac function. This supports further evaluation of NAD + -boosting therapies as targeted interventions for postmenopausal women at risk of heart failure with preserved ejection fraction. Impaired PGC-1α–pAMPK signaling and the restorative role of nicotinamide in a murine model of postmenopausal metabolic cardiac dysfunction. Schematic representation of impaired mitochondrial biogenesis and fatty acid metabolism resulting from reduced NAD + levels in postmenopausal states. Decreased NAD + availability leads to suppression of SIRT1 and pAMPK signaling, reducing PGC-1α activity and increasing oxidative stress through lower antioxidant defenses (↓ mnSOD, ↓ Cyt C). These changes promote inflammation, fibrosis, and apoptosis, contributing to diastolic dysfunction, microvascular disease, and poorer postoperative outcomes in women undergoing cardiac surgery. In the experimental murine model, ovariectomized mice fed a high-fat diet (HFD) exhibit reduced cardiac PGC-1α and pAMPK signaling. Seven days of intraperitoneal nicotinamide injections restore NAD + levels, upregulate PGC-1α and pAMPK, and improve mitochondrial function and ejection fraction (EF), highlighting the potential therapeutic role of NAD + augmentation in reversing postmenopausal cardiac metabolic impairment. • Postmenopausal women show impaired PGC-1α/AMPK signaling after surgery. • NAD + depletion contributes to diastolic dysfunction and fibrosis in females. • Ovariectomy + high-fat diet mice replicate postmenopausal cardiac stress. • Nicotinamide restores NAD + , PGC-1α/AMPK activity, and cardiac performance. • Findings highlight NAD + boosting as a non-hormonal therapeutic strategy.

Source: Journal of Molecular and Cellular Cardiology Plus

DOI: 10.1016/j.jmccpl.2025.100831