P16ink4a overexpression ameliorates cardiac remodeling of mouse following myocardial infarction via CDK4/pRb pathway.

Abstract

BACKGROUND:

P16ink4a can accumulate in senescent cells and can be induced by different oncogenic stimulations. These functions make p16ink4a a biomarker of senescence and cancer. However, the exact role of p16ink4a remains unclear in cardiovascular disease. This study was aimed to investigate the role of p16ink4a in cardiac remodeling after myocardial infarction (MI).

METHODS:

In vivo, gain and loss of function experiments using p16ink4a overexpression and knockdown adenovirus were induced to determine the effect of p16ink4a on cardiac structure and function after MI. The in vitro effects of p16ink4a were evaluated by overexpression and knockdown adenovirus of p16ink4a on isolated neonatal mouse cardiac myocytes (NMCMs) and neonatal mouse cardiac fibroblasts (NMCFs).

RESULTS:

Expression level of p16ink4a was increased after MI and enriched in the infarction area. In vivo, overexpression of p16ink4a protected, while knockdown of p16ink4a worsened cardiac function. In vitro, p16ink4a did not influence the hypertrophy of NMCMs. Overexpression of p16ink4a inhibited the proliferation and migration of NMCFs and reduced the level of collagen I and α-SMA. Consistently, knockdown of p16ink4a in vitro displayed the opposite effects. Further mechanism studies revealed that p16ink4a affected the expression level of cyclin-dependent kinase 4 (CDK4) and phosphorylation of retinoblastoma (pRb), which could be a potential pathway in regulating cardiac remodeling after MI.

CONCLUSION:

Overexpression of 16ink4a in cardiac fibroblasts can ameliorate cardiac dysfunction and attenuate pathological cardiac remodeling in mice after MI by regulating the p16ink4a/CDK4/pRb pathway.

• Authors: Jianzhou Shi, Jiateng Sun, Liu Liu, Tiankai Shan, Haoyu Meng, Tongtong Yang, Sibo Wang, Tianwen Wei, Bingrui Chen, Yao Ma, Qiming Wang, Hao Wang, Jiabao Liu, Liansheng Wang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 595 Pg. 62-68 (03 05 2022) ISSN: 1090-2104 [Electronic] United States
• PMID: 35093641 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Cyclin-Dependent Kinase Inhibitor p16
• Retinoblastoma Protein
• Cyclin-Dependent Kinase 4

Topics

• Animals
• Animals, Newborn
• Cell Movement (genetics)
• Cell Proliferation (genetics)
• Cells, Cultured
• Cyclin-Dependent Kinase 4 (genetics, metabolism)
• Cyclin-Dependent Kinase Inhibitor p16 (genetics, metabolism)
• Fibroblasts (cytology, metabolism)
• Gene Expression
• Male
• Mice, Inbred ICR
• Myocardial Infarction (genetics, metabolism, physiopathology)
• Myocytes, Cardiac (cytology, metabolism)
• Phosphorylation
• Retinoblastoma Protein (genetics, metabolism)
• Signal Transduction (genetics)
• Ventricular Remodeling (genetics)