[Mechanism study of Linggui Zhugan Decoction in improving post-myocardial infarction heart failure by modulating...

Mitochondrial calcium(mtCa~(2+)) overload constitutes a core pathological process in the initiation and progression of heart failure(HF) following myocardial infarction(MI). Abnormal accumulation of the lipid peroxide 4-hydroxynonenal(4-HNE) mediated by monoamine oxidase A(MAOA), as well as dysfunction of the mtCa~(2+) uniporter(MCU), can both induce mtCa~(2+) overload. Linggui Zhugan Decoction(LGZGD), a classical traditional Chinese medicine prescription for the treatment of cardiovascular diseases, is extensively used to manage post-MI HF. However, its regulatory effects on mtCa~(2+) homeostasis and the underlying molecular mechanisms remain unclear. In the present study, a rat model of post-MI HF and a H_2O_2-induced oxidative stress model in H9C2 cardiomyocytes were established, combined with MAOA overexpression and knockdown validation experiments, to systematically investigate the cardioprotective mechanisms of LGZGD. The results revealed that LGZGD significantly improved cardiac systolic function in MI rats(P<0.01), reduced creatine kinase(CK) and lactate dehydrogenase(LDH) activities(P<0.05), alleviated myocardial pathological injury, and significantly decreased the level of the oxidative stress marker 4-HNE while restoring the content of the antioxidant glutathione(GSH)(P<0.05). In vitro experiments further demonstrated that LGZGD-medicated serum effectively suppressed apoptosis in H9C2 cardiomyocytes, restored mitochondrial membrane potential(P<0.01), and promoted mitophagy to eliminate damaged mitochondria. Moreover, LGZGD markedly inhibited MAOA expression and activation, reduced 4-HNE accumulation, subsequently downregulated MCU-mediated mtCa~(2+) overload, and effectively maintained mtCa~(2+) homeostasis(P<0.01). MAOA functional modulation experiments further demonstrated that MAOA knockdown mimicked the protective effects of LGZGD, whereas MAOA overexpression exacerbated cardiomyocyte injury, and LGZGD partially reversed this adverse effect(P<0.05). Collectively, this study confirms that LGZGD significantly ameliorates post-MI HF and oxidative stress-induced cardiomyocyte injury, with the underlying mechanism closely associated with modulation of the MAOA/4-HNE/MCU pathway, clearance of damaged mitochondria, and maintenance of mtCa~(2+) homeostasis.