Mas receptor activation regulates the functional phenotype of myocardial macrophages through the Akt/Nrf2 signaling pathway to alleviate sepsis-induced cardiomyopathy

BACKGROUND: Sepsis-induced cardiomyopathy (SIC) has high mortality due to uncontrolled cardiac inflammation and macrophage-mediated mitochondrial damage. The Ang-(1–7)/Mas receptor (MasR) axis exhibits anti-inflammatory effects, but its role in modulating macrophage phenotypes in SIC remains unclear. This study aimed to determine if MasR activation confers cardioprotective effects in SIC via the macrophage polarization-regulating Akt/Nrf2 pathway. METHODS: Blood samples from healthy controls and patients with SIC were analyzed for MasR expression on monocytes via flow cytometry. SIC was induced in mice using the cecal ligation and puncture model, with pretreatment using the MasR agonist AVE0991. Cardiac macrophage-specific MasR overexpression was achieved using an AAV9 vector. Cardiac function, myocardial injury, macrophage phenotypes, mitochondrial morphology, and apoptosis were assessed by echocardiography, histopathology, transmission electron microscopy, TUNEL staining, and multiplex flow cytometry. Bone marrow-derived macrophages (BMDM) were exposed to LPS and treated with AVE0991 and the Nrf2 inhibitor ML385 in vitro. The role of the Akt/Nrf2 pathway in macrophage polarization and cardiomyocyte protection was confirmed through Western blot, flow cytometry, and a BMDM-H9c2 cardiomyocyte co-culture system. RESULTS: MasR expression on monocytes was significantly elevated in patients with SIC and correlated positively with IL-6, lactate, and TnI levels. In SIC mice, pretreatment with AVE0991 or cardiac macrophage-specific MasR overexpression significantly improved survival, enhanced cardiac function, and reduced myocardial injury and apoptosis. Mechanistically, MasR activation enhanced Akt phosphorylation and Nrf2 nuclear translocation in both myocardial tissue and BMDM, promoting a shift in cardiac macrophages from an inflammatory M1 state toward a protective M2 state, thereby reducing inflammatory infiltration. Additionally, MasR activation preserved mitochondrial homeostasis, enhancing mitochondrial membrane potential and ATP production. The Nrf2 inhibitor ML385 completely abolished the protective effects induced by AVE0991. In the co-culture system, conditioned medium from AVE0991-treated BMDM alleviated oxidative stress, mitochondrial damage, and apoptosis in H9c2 cells. CONCLUSIONS: MasR activation alleviates SIC by initiating the Akt/Nrf2 signaling axis, reprogramming cardiac macrophages towards a protective M2 phenotype, thereby reducing myocardial inflammation, enhancing mitochondrial function, and inhibiting cardiomyocyte apoptosis. This study suggests that targeting the MasR-Akt/Nrf2-macrophage axis may offer a novel therapeutic strategy for SIC.