The calcineurin-myocyte enhancer factor 2c pathway mediates cardiac hypertrophy induced by endoplasmic reticulum stress in neonatal rat cardiomyocytes

Abstract

The calcineurin-myocyte enhancer factor 2c pathway mediates cardiac hypertrophy induced by endoplasmic reticulum stress in neonatal rat cardiomyocytes. Am J Physiol Heart Circ Physiol 298: H1499 -H1509, 2010. First published March 5, 2010; doi:10.1152/ajpheart.00980.2009.-Endoplasmic reticulum (ER) stress (ERS) is involved in various cardiovascular diseases. Our previous study verified that ERS took part in the development of cardiac hypertrophy; however, its mechanism is still unclear. This study aimed to investigate the roles of the calcineurin (CaN) signal pathway in hypertrophy induced by the ERS inductor thapsigargin (TG) in neonatal cardiomyocytes from Sprague-Dawley rats. Investigation of ER chaperone expression, ER staining, and calreticulin immunoflourescence were used to detect the ERS response. mRNA expression of atrial natriuretic peptide and brain natriuretic peptide, total protein synthesis rate, and cell surface area were used to evaluate cardiac hypertrophy induced by TG. TG induced a significant ERS response along with hypertrophy in a doseand time-dependent manner in cardiomyocytes, which was verified by treatment with tunicamycin, another ERS inducer. Furthermore, TG induced a significant elevation of the intracellular Ca 2ϩ level, CaN activation, and myocyte enhancer factor 2c (MEF2c) expression in a dose-and time-dependent manner in cardiomyocytes. Cyclosporine A, a CaN inhibitor, markedly suppressed MEF2c nuclear translocation and inhibited TG-induced hypertrophy. These results demonstrate that ERS induces cardiac hypertrophy and that the CaN-MEF2c pathway is involved in ERS-induced hypertrophy in cardiomyocytes. thapsigargin CARDIAC HYPERTROPHY is an adaptive response triggered by many physiological and pathological conditions. However, epidemiological data have indicated that chronic cardiac hypertrophy is associated with an increase in the cardiovascular morbidity/mortality risk. Evidence has shown that many factors, including Ca 2ϩ overload, abnormal protein synthesis, and apoptosis, are involved in the development of cardiac hypertrophy (20). The endoplasmic reticulum (ER), called the sarcoplasmic reticulum (SR) in cardiac myocytes, is an organelle regulating intracellular Ca 2ϩ , folding of secreted and membrane protein, and cell apoptosis. Various stimuli, such as ER Ca 2ϩ depletion, elevated protein synthesis, ischemia, and hypoxia, disturb ER homeostasis and result in ER stress (ERS). In response to ERS, ER chaperones such as calreticulin (CRT) and glucose-regulated proteins (GRPs) are upregulated to enhance the ability of the ER to regulate the intracellular Ca 2ϩ level and handle the unfolded proteins, which is cardioprotective. However, when ERS is excessive and/or prolonged, the ER-related apoptotic process is initiated by the induction of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) and caspase-12 activation. Protein kinase R-like ER kinase (PERK) is an important ER transmembrane protein; the relocation of GRP78 from the luminal domain of PERK to misfolded ...

Polyamine Depletion Attenuates Isoproterenol-Induced Hypertrophy and Endoplasmic Reticulum Stress in Cardiomyocytes

“…The CHOP and caspase-12 proteins are distal effectors of ERS response mediating apoptotic signals. There is extensive evidence indicating ERS markers, GRP78 and CHOP are increased in cases of cardiac hypertrophy and incidences of heart failure [25,26]. ERS has been shown to lead to apoptosis in these processes and as a link between apoptosis, cardiomyocyte loss, ventricular remodeling, and deterioration of systolic performance in multiple experimental models [27,28].…”

Partial Inactivation of Cardiac 14-3-3 Protein <i>in vivo</i> Elicits Endoplasmic Reticulum Stress (ERS) and Activates ERS-initiated Apoptosis in ERS-induced Mice

“…To test whether 14-3-3 protein involved in the ERS response during cardiac ERS through SERCA2, we further induced ERS using thapsigargin. Thapsigargin has been known to inhibit contraction and Ca 2+ transient in cardiac cells by specific inhibition of the SERCA pump [25], to increase protein levels of ER chaperones in cultured cardiac myocytes [5] and to elicit ERS in time and dose-dependent manner in the neonatal rat cardiomyocytes [26]. In our study, we have shown that the inhibition of SERCA2 using thapsigargin significantly increased cardiac expression of GRP78 protein in the DN14-3-3 mice compared with the WT mice.…”

4-PBA prevents pressure overload-induced myocardial hypertrophy and interstitial fibrosis by attenuating endoplasmic reticulum stress

“…The activation of ER stress in the heart is associated with myocardial apoptosis [4,5], hypertrophy [6,7], and fibrosis [8,9], the pathological processes common in development of ischemic and hypertrophic heart diseases. Therefore, inhibiting ER stress may be an important consideration in developing treatments for ischemic or hypertrophic cardiomyopathy.…”