title: The calcineurin-myocyte enhancer factor 2c pathway mediates cardiac hypertrophy induced by endoplasmic reticulum stress in neonatal rat cardiomyocytes.
abstract: 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 immunofluorescence 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 dose- and 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(2+) 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.
authors.affiliation: Department of Pathophysiology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China.
authors.forename: Zhen-Ying
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Xiu-Hua
authors.initials: XH
authors.lastname: Liu
authors.forename: Wei-Cheng
authors.initials: WC
authors.lastname: Hu
authors.forename: Fei
authors.initials: F
authors.lastname: Rong
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Wu
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D019703:Calcineurin / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000473:pathology*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D064326:MEF2 Transcription Factors; D032383:Myocytes, Cardiac / Q000502:physiology*; D018006:Myogenic Regulatory Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D014415:Tunicamycin; D012313:RNA; D019284:Thapsigargin; D016572:Cyclosporine; D007770:L-Lactate Dehydrogenase; D019703:Calcineurin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium