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

Abstract

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.

Proteomic Profiling of Dilated Cardiomyopathy Plasma Samples ─ Searching for Biomarkers with Potential to Predict the Outcome of Therapy

“…We have noted also significant down-regulation of gelsolin (GSN), a known biomarker of rheumatic carditis, ficolin-3 (FCN3), which was also down-regulated in heart failure due to DCM or coronary heart disease, peptidase inhibitor 16 (PI16), known to be down-regulated in myocardial infarction and DCM, fibronectin (FN1), which is connected to coronary heart disease and DCM, or kallistatin (SERPINA4), which down-regulation in heart failure was connected to decreased survival time …”

“…43 Its reduced expression was observed in the heart tissues of DCM patients. 44 We have noted also significant down-regulation of gelsolin (GSN), a known biomarker of rheumatic carditis, 45 ficolin-3 (FCN3), which was also down-regulated in heart failure due to DCM or coronary heart disease, 46 peptidase inhibitor 16 (PI16), known to be down-regulated in myocardial infarction 47 and DCM, 41 fibronectin (FN1), which is connected to coronary heart disease 48 and DCM, 49 or kallistatin (SERPINA4), which down-regulation in heart failure was connected to decreased survival time. 50 To test the predictive value of DCM-associated proteins, we performed the logistic regression with elastic net optimization approach.…”

Peptidase inhibitor 16 promotes proliferation of pancreatic ductal adenocarcinoma cells through OASL signaling

“…Pi16 was originally found to be a class of proteins of approximately 400 amino acids that can bind to PSP94 secreted in the blood of prostate cancer patients, located on human chromosome 6p21.2 5,6 . Subsequent studies have shown that Pi16 can also be secreted by myocardial fibroblasts and coronary endothelial cells and is found in cytoplasmic vesicles 23–25 . Interestingly, in addition to being a secreted protein, Pi16 also functions as a transmembrane protein.…”

“…Recent reports indicate that Pi16 is involved in a variety of pathophysiological processes and plays an important role in a variety of signaling pathways. Since Frost et al first discovered that Pi16 is highly expressed in cardiomyocytes, an increasing number of studies have confirmed that Pi16 not only participates in heart failure, myocardial hypertrophy, and myocardial infarction but also inhibits the inflammatory response of human coronary endothelial cells and cardiomyocyte fibrosis 24,25 . The role of Pi16 in tumors is also being explored.…”

Regulatory role of PI16 in autoimmune arthritis and intestinal inflammation: implications for Treg cell differentiation and function

“…The identification of pi16 in recurrent prostate cancer has established its significance as a prognostic indicator, exhibiting a positive correlation with relapse-free survival [ 24 , 25 ]. Subsequently, PI16 was highly upregulated in cardiac disease and can inhibit the growth of cardiomyocytes [ 26 ] or attenuated left ventricular injury and remodeling after myocardial infarction [ 27 , 28 ]. In recent research, the function of PI16 in different organs and tissues is gradually being elucidated.…”