Abstract
Humoral factors regulating cardiac myocytes have not yet been fully elucidated. Using mass spectrometry, we analyzed peptides released from primary neonatal rat cardiac fibroblasts to identify a 24-amino-acid peptide with an intramolecular disulfide bond. It is derived from the C-terminal end of integral membrane protein 2A (ITM2A), a single-pass type II membrane protein; the peptide sequence is identical between humans and rodents and N-terminally flanked by conserved dibasic residues KR. The ITM2A peptide stimulated secretion of atrial natriuretic peptide (ANP), the predominant hormone produced by cardiac myocytes, in a Langendorff rat heart perfusion system as well as a primary culture of neonatal rat ventricular myocytes. These ANP secretion changes were not accompanied by an alteration in the beating rate, a key determinant of ANP secretion. In a mouse cardiac infarction model, both plasma ANP concentration and ITM2A gene expression in heart tissue reached a peak level on day 7 after operation. Our findings provide new insight into cardiac cell-to-cell communication that regulates ANP secretion. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-43576-8.