Circulation Research. 2002;91:640-647
Published online before print September 5, 2002, doi: 10.1161/01.RES.0000035854.11082.01
Published online before print September 5, 2002, doi: 10.1161/01.RES.0000035854.11082.01
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© 2002 American Heart Association, Inc.
Integrative Physiology |
c-Jun N-Terminal Kinase Activation Mediates Downregulation of Connexin43 in Cardiomyocytes
From the Department of Cell Biology (X.G., X.W.), The Scripps Research Institute, La Jolla, Calif; the Departments of Pathology and Pediatrics (D.L.L., J.E.S.), Washington University, St. Louis, Mo; the Department of Physiology (B.G.P., Y.W.), University of Maryland School of Medicine, Baltimore; and the Department of Pharmacology (J.H.B.), University of California, San Diego.
Correspondence to Yibin Wang, PhD, Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201. E-mail ywang001{at}umaryland.edu
Loss of gap junctions and impaired intercellular communication are characteristic features of pathological remodeling in heart failure as a result of stress or injury, yet the underlying regulatory mechanism has not been identified. Here, we report that in cultured myocytes, rapid loss of the gap junction protein connexin43 (Cx43) occurs in conjunction with the activation of c-Jun N-terminal kinase (JNK), a stress-activated protein kinase, on stress stimulation. To investigate the specific role of JNK activation in the regulation of connexin in cardiomyocytes, an activated mutant of mitogen-activated protein kinase kinase 7 (mutant D), a JNK-specific upstream activator, was expressed in myocytes by adenovirus-mediated gene transfer. JNK activation in infected cardiomyocytes resulted in significant reduction of Cx43 expression at both mRNA and protein levels and impaired cell-cell communication. To evaluate the role of JNK in the regulation of Cx43 expression and gap junction structure in vivo, a Cre-LoxP–mediated gene-switch system was used to establish a transgenic animal model with targeted activation of JNK in ventricular myocardium. The transgenic hearts exhibited significant downregulation of Cx43 expression and loss of gap junctions in myocardium that may contribute to the cardiac dysfunction and premature death phenotype. Our report represents the first evidence, both in vitro and in vivo, implicating JNK as an important mediator of stress-induced Cx43 downregulation and impaired intercellular communication in the failing heart.
Key Words: gap junctions • connexin43 • c-Jun N-terminal kinase • stress response • heart failure
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