Peptidase Inhibitor 16 Attenuates Left Ventricular Injury and Remodeling After Myocardial Infarction by Inhibiting the HDAC1-Wnt3a-β-Catenin Signaling Axis

Background Myocardial infarction (MI) is a Cardiovascular Disease with high morbidity and mortality. PI16 (peptidase inhibitor 16), as a secreted protein, is highly expressed in heart diseases such as heart failure. However, the functional role of PI16 in MI is unknown. This study aimed to investigate the role of PI16 after MI and its underlying mechanisms. Methods and Results PI16 levels after MI were measured by enzyme-linked immunosorbent assay and immunofluorescence staining, which showed that PI16 was upregulated in the plasma of patients with acute MI and in the infarct zone of murine hearts. PI16 gain- and loss-of-function experiments were used to investigate the potential role of PI16 after MI. In vitro, PI16 overexpression inhibited oxygen-glucose deprivation-induced Apoptosis in neonatal rat cardiomyocytes, whereas knockdown of PI16 exacerbated neonatal rat cardiomyocyte Apoptosis. In vivo, left anterior descending coronary artery ligation was performed on PI16 transgenic mice, PI16 knockout mice, and their littermates. PI16 transgenic mice showed decreased cardiomyocyte Apoptosis at 24 hours after MI and improved left ventricular remodeling at 28 days after MI. Conversely, PI16 knockout mice showed aggravated infract size and remodeling. Mechanistically, PI16 downregulated Wnt3a (wingless-type MMTV integration site family, member 3a)/β-catenin pathways, and the antiapoptotic role of PI16 was reversed by recombinant Wnt3a in oxygen-glucose deprivation-induced neonatal rat cardiomyocytes. PI16 also inhibited HDAC1 (class I histone deacetylase) expression, and overexpression HDAC1 abolished the inhibition of Apoptosis and Wnt signaling of PI16. Conclusions In summary, PI16 protects against cardiomyocyte Apoptosis and left ventricular remodeling after MI through the HDAC1-Wnt3a-β-catenin axis.

HDAC1; PI16; cardiomyocyte apoptosis; myocardial infarction; remodeling.