Alteration in ventricular pressure stimulates cardiac repair and remodeling

J Mol Cell Cardiol. 2019 Aug:133:174-187. doi: 10.1016/j.yjmcc.2019.06.006. Epub 2019 Jun 17.

Abstract

The mammalian heart undergoes complex structural and functional remodeling to compensate for stresses such as pressure overload. While studies suggest that, at best, the adult mammalian heart is capable of very limited regeneration arising from the proliferation of existing cardiomyocytes, how myocardial stress affects endogenous cardiac regeneration or repair is unknown. To define the relationship between left ventricular afterload and cardiac repair, we induced left ventricle pressure overload in adult mice by constriction of the ascending aorta (AAC). One week following AAC, we normalized ventricular afterload in a subset of animals through removal of the aortic constriction (de-AAC). Subsequent monitoring of cardiomyocyte cell cycle activity via thymidine analog labeling revealed that an acute increase in ventricular afterload induced cardiomyocyte proliferation. Intriguingly, a release in ventricular overload (de-AAC) further increases cardiomyocyte proliferation. Following both AAC and de-AAC, thymidine analog-positive cardiomyocytes exhibited characteristics of newly generated cardiomyocytes, including single diploid nuclei and reduced cell size as compared to age-matched, sham-operated adult mouse myocytes. Notably, those smaller cardiomyocytes frequently resided alongside one another, consistent with local stimulation of cellular proliferation. Collectively, our data demonstrate that adult cardiomyocyte proliferation can be locally stimulated by an acute increase or decrease of ventricular pressure, and this mode of stimulation can be harnessed to promote cardiac repair.

Keywords: Aortic constriction; Cardiac remodeling; Cardiac repair; Cardiomyocyte proliferation; Hypertrophy; LV pressure overload.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Cardiomegaly / etiology
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Cell Proliferation
  • Disease Models, Animal
  • Echocardiography
  • Fluorescent Antibody Technique
  • Gene Expression
  • Heart Ventricles / metabolism*
  • Heart Ventricles / pathology*
  • Hypertrophy, Left Ventricular / etiology
  • Hypertrophy, Left Ventricular / metabolism
  • Hypertrophy, Left Ventricular / pathology
  • Mice
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Oxidative Stress
  • Ventricular Pressure*
  • Ventricular Remodeling*

Substances

  • Biomarkers