Senescence as a novel mechanism involved in β-adrenergic receptor mediated cardiac hypertrophy

PLoS One. 2017 Aug 4;12(8):e0182668. doi: 10.1371/journal.pone.0182668. eCollection 2017.

Abstract

Pathological cardiac hypertrophy used to be elucidated by biomechanical, stretch-sensitive or neurohumoral mechanisms. However, a series of hints have indicated that hypertrophy process simulates senescence program. However, further evidence need to be pursued. To verify this hypothesis and examine whether cardiac senescence is a novel mechanism of hypertrophy induced by isoproterenol, 2-month-old male Sprague Dawley rats were subjected to isoproterenol infusion (0.25mg/kg/day) for 7 days by subcutaneous injection). Key characteristics of senescence (senescence-associated β-galactosidase activity, lipofuscin, expression of cyclin-dependent kinase inhibitors) were examined in cardiac hypertrophy model. Senescence-like phenotype, such as increased senescence-associated β-galactosidase activity, accumulation of lipofuscin and high levels of cyclin-dependent kinase inhibitors (e.g. p16, p19, p21 and p53) was found along the process of cardiac hypertrophy. Cardiac-specific transcription factor GATA4 increased in isoproterenol-treated cardiomyocytes as well. We further found that myocardial hypertrophy could be inhibited by resveratrol, an anti-aging compound, in a dose-dependent manner. Our results showed for the first time that cardiac senescence is involved in the process of pathological cardiac hypertrophy induced by isoproterenol.

MeSH terms

  • Animals
  • Cardiomegaly / chemically induced
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology*
  • Cellular Senescence* / drug effects
  • Cyclin-Dependent Kinase Inhibitor Proteins / genetics
  • GATA4 Transcription Factor / genetics
  • Gene Expression Regulation / drug effects
  • Isoproterenol / pharmacology
  • Male
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, beta / metabolism*
  • Resveratrol
  • Stilbenes / pharmacology

Substances

  • Cyclin-Dependent Kinase Inhibitor Proteins
  • GATA4 Transcription Factor
  • Gata4 protein, rat
  • Receptors, Adrenergic, beta
  • Stilbenes
  • Isoproterenol
  • Resveratrol

Grant support

This work was supported by the grants from the National Basic Research Program of China (grant number. 2014CBA02003) and the National Natural Science Foundation of China (grant numbers. 81672091, 81541142, 81471893, 81270157, 91539123, 81070078). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.