Acute myocardial infarction (AMI) is one of the leading causes of cardiovascular death worldwide. AMI with cardiomyopathy is accompanied by a poor long-term prognosis. However, limited studies have focused on the mechanism of cardiomyopathy associated with AMI. Pericytes are important to the microvascular function in the heart, yet little attention has been paid to their function in myocardial infarction until now. In this study, we integrated single-cell data from individuals with cardiomyopathy and myocardial infarction (MI) GWAS data to reveal the potential function of pericytes in cardiomyopathy-associated MI. We found that pericytes were concentrated in the left atrium and left ventricle tissues. DLC1/GUCY1A2/EGFLAM were the top three uniquely expressed genes in pericytes (p < 0.05). The marker genes of pericytes were enriched in renin secretion, vascular smooth muscle contraction, gap junction, purine metabolism, and diabetic cardiomyopathy pathways (p < 0.05). Among these pathways, the renin secretion and purine metabolism pathways were also found in the process of MI. In cardiomyopathy patients, the biosynthesis of collagen, modulating enzymes, and collagen formation were uniquely negatively regulated in pericytes compared to other cell types (p < 0.05). COL4A2/COL4A1/SMAD3 were the hub genes in pericyte function involved in cardiomyopathy and AMI. In conclusion, this study provides new evidence about the importance of pericytes in the pathogenesis of cardiomyopathy-associated MI. DLC1/GUCY1A2/EGFLAM were highly expressed in pericytes. The hub genes COL4A2/COL4A1/SMAD3 may be potential research targets for cardiomyopathy-associated MI.

Heart failure, the common end-stage of cardiovascular diseases, features cardiac fibrosis. Transforming growth factor-β3 (TGFB3), a key TGFB/SMAD ligand, is upregulated in cardiac disorders, but its cellular source and precise role are debated. This study examined TGFB3 in human and mouse heart failure tissues. Histological and molecular analyses showed its increase mainly from cardiomyocytes, induced by angiotensin II. Circulating TGFB3 in patients positively correlated with plasma proBNP, a heart failure severity marker. A cardiomyocyte-specific TGFB3 knockout mouse model showed its absence worsens cardiac dysfunction and fibrosis under pressure overload. Mechanically, TGFB3 competes with TGFB1 for receptors, reducing Smad3 phosphorylation and profibrotic gene activation. Loss of TGFB3 in cardiomyocytes increased expression of profibrotic mediators such as CTGF and SERPINE1, ultimately accelerating fibrotic remodeling during HF progression. These findings identify cardiomyocyte-derived TGFB3 as a crucial endogenous modulator that protects against pathological cardiac fibrosis and highlight its therapeutic potential in HF.