Imbalance of the CaSR-SIRT3 axis exacerbates ventricular remodeling by promoting macrophage M1 polarization via the AMPK signaling pathway post-myocardial infarction.

Ventricular remodeling post-myocardial infarction (MI) is closely associated with immune responses; however, the underlying mechanisms remain incompletely understood. This study investigated whether the calcium-sensing receptor (CaSR) regulates macrophage (MΦ) polarization via the SIRT3-AMPK axis and its role in post-MI ventricular remodeling. Wistar rats were randomly divided into sham, MI, MI + Calhex231 and MI + RSV groups. Proteomics revealed marked SIRT3 down-regulation after MI, and GO analysis linked it to Ca2+ and MΦ polarization. Compared with sham groups, MI rats showed significantly increased CaSR, LVEDD, LVESD, myocardial fibrosis, Collagen III, M1 markers (CD86 and iNOS) and p-AMPK/AMPK, and decreased SIRT3, EF, FS and M2 markers (CD163 and IL-10); Calhex231 and RSV significantly reversed these changes. Immunofluorescence revealed co-localization of MΦ subsets with CaSR and SIRT3 in post-MI myocardium. In vitro, LPS increased CaSR, p-AMPK/AMPK and M1 markers and decreased SIRT3 and M2 markers; Calindol exacerbated, while Calhex231 ameliorated these effects. RSV or 3-TYP respectively reduced or increased LPS-induced p-AMPK/AMPK elevation and M1 markers without affecting CaSR expression. Dor reduced LPS-mediated p-AMPK/AMPK expression and M1 polarization without altering CaSR or SIRT3. Mechanistically, CaSR regulated SIRT3 transcriptionally, and SIRT3 directly deacetylated SOD2 at K68 and modulated the NAD+/NADH ratio, thereby suppressing AMPK phosphorylation and shifting MΦ polarization from M1 toward M2. These findings were further supported by qPCR and ELISA, which confirmed changes in M1/M2 marker gene expression and cytokine secretion. Co-culture experiments confirmed that M2-skewed MΦ protected cardiomyocytes from injury and suppressed fibroblast activation. These findings demonstrate that post-MI CaSR activation in MΦ regulates MΦ polarization via the SIRT3-mediated AMPK pathway, thereby modulating cardiac inflammation and fibrosis and ultimately ventricular remodeling, providing a potential therapeutic target for post-MI heart failure.