Zhenwu Decoction improves myocardial energy metabolism and mitochondrial integrity in pressure overload-induced heart failure partly through AMP-activated protein kinase signaling.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Zhenwu Decoction (ZWD), recorded in the Shang Han Lun, is traditionally used for yang deficiency with fluid retention, a pattern relevant to congestion and impaired cardiac function. Its mitochondrial mechanism in pressure-overload heart failure remains unclear. AIM OF THE STUDY: To evaluate the cardioprotective effects of ZWD and the contribution of AMP-activated protein kinase (AMPK)-related signaling. MATERIALS AND METHODS: Male C57BL/6J mice subjected to transverse aortic constriction received low-, medium-, or high-dose ZWD (4.32, 8.64, or 17.28 g/kg/day, respectively) or the positive control captopril. Cardiac function, remodeling, oxidative stress, energy metabolites, mitochondrial ultrastructure, transcriptomics, and metabolomics were assessed. In angiotensin II-injured H9c2 cardiomyoblasts, small interfering RNA-mediated AMPK silencing was used to assess pathway dependence. RESULTS: ZWD improved systolic function and reduced ventricular dilation, injury biomarkers, collagen accumulation, and oxidative imbalance, with the most evident effects at the high dose. It increased adenosine triphosphate and acetyl-coenzyme A, reduced adenosine diphosphate and adenosine monophosphate, and preserved mitochondrial ultrastructure. These changes were accompanied by increased AMPK phosphorylation and sirtuin 1 abundance and reduced dynamin-related protein 1 phosphorylation. Multi-omics analyses identified treatment-associated changes in energy-related pathways. AMPK silencing attenuated, but did not completely abolish, the mitochondrial and metabolic effects of ZWD. CONCLUSIONS: ZWD ameliorated pressure-overload cardiac dysfunction and improved myocardial energy homeostasis and mitochondrial integrity. AMPK silencing partially attenuated the cellular response, supporting AMPK involvement in these protective effects, alongside increased sirtuin 1 abundance and reduced dynamin-related protein 1 phosphorylation.

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