Chronic social stress induces cardiomyocyte contractile dysfunction and intracellular Ca2+ derangement in rats

Abstract

Chronic psychosocial stress triggers cardiovascular diseases although underlying mechanisms are still elusive. This study examined the effect of social stress on cardiomyocyte contractile function and pathological changes in myocardium using the visible burrow system (VBS) model. Chronic social stress was induced using a mixed-sex VBS housing in adult Sprague–Dawley (SD) rats. Contractile and intracellular Ca2+ properties were evaluated in isolated cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), maximal velocity of shortening/relengthening (± dL/dt), Fura-2 fluorescence intensity, and intracellular Ca2+ decay. Myocardial histology was evaluated using Masson trichrome staining. Social stress led to depressed PS, ± dL/dt, shortened TPS and prolonged TR90 compared with the unstressed controls. Baseline and electrically-stimulated rise in Ca2+ were reduced whereas intracellular Ca2+ decay was delayed in stressed rats. Histological analyses exhibited overt interstitial fibrosis and cardiomyocyte hypertrophy in stressed rats. The GSH/GSSG ratio (indicative of oxidative stress status) was reduced whereas oxidative protein carbonyl formation was elevated in stressed rats. Western blot analysis showed unchanged expression of superoxide dismutase 1 (SOD1), β1-adrenoceptor (β1-AR) levels, reduced sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) levels, and elevated phosphorylation of the stress signaling protein kinase JNK but not ERK in myocardium from stressed rats. Short-term in vitro treatment of cardiomyocytes with the stress inducer phenylephrine mimicked cell damage and intracellular Ca2+ mishandling, the effects of which were mitigated by antioxidant, JNK inhibition, carvedilol and SERCA2a adenovirus. These findings indicate that chronic social stress is detrimental to cardiac structure and function possibly via mechanisms associated with oxidative injury and intracellular Ca2+ mishandling.