Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction

PLoS One. 2013 Sep 11;8(9):e74535. doi: 10.1371/journal.pone.0074535. eCollection 2013.


Senescence is a recognized mechanism of cardiovascular diseases; however, its contribution to myocardial fibrosis and rupture after infarction and the underlying mechanisms remain unclear. Here we showed that senescent cardiac fibroblasts markedly accumulated in heart after myocardial infarction. The expression of key senescence regulators, especially p53, was significantly up-regulated in the infarcted heart or hypoxia-treated fibroblasts. Furthermore, knockdown of endogenous p53 by siRNA in fibroblasts markedly reduced hypoxia-induced cell senescence, cytokine expression but increased collagen expression, whereas increased expression of p53 protein by adenovirus infection had opposite effects. Consistent with in vitro results in cardiac fibroblasts, p53 deficiency in vivo significantly decreased the accumulation of senescent fibroblasts, the infiltration of macrophages and matrix metalloproteinases, but enhanced collagen deposition after myocardial infarction. In conclusion, these results suggest that the p53-mediated fibroblast senescence limits cardiac collagen production, and inhibition of p53 activity could represent a novel therapeutic target to increase reparative fibrosis and to prevent heart rupture after myocardial infarction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Animals
  • Cell Hypoxia / genetics
  • Cell Movement
  • Cells, Cultured
  • Cellular Senescence / genetics*
  • Collagen / genetics
  • Collagen / metabolism
  • Disease Models, Animal
  • Endomyocardial Fibrosis / etiology
  • Endomyocardial Fibrosis / genetics*
  • Endomyocardial Fibrosis / metabolism
  • Endomyocardial Fibrosis / pathology
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Gene Expression Regulation
  • Genetic Vectors
  • Male
  • Mice
  • Mice, Knockout
  • Myocardial Infarction / complications
  • Myocardial Infarction / genetics*
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardium / metabolism*
  • Myocardium / pathology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics*


  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • Collagen

Grant support

This study was supported by grants from the Chinese Ministry of Science and Technology (2012CB945104, 2012CB517802), National Natural Science Foundation of China (81230006, 31090363, 81025001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.