title: Gap junction remodeling and spironolactone-dependent reverse remodeling in the hypertrophied heart.
abstract: Pressure overload is a common pathological insult to the heart and the resulting hypertrophy is an independent risk factor for sudden cardiac death. Gap junction remodeling (GJR) has been described in hypertrophied hearts; however, a detailed understanding of the remodeling process and its effects on impulse propagation is lacking. Moreover, there has been little progress developing therapeutic strategies to diminish GJR. Accordingly, transverse aortic banding (TAC) was performed in mice to determine the effects of progressive pathological hypertrophy on connexin (Cx)43 expression, posttranslational phosphorylation, gap junction assembly, and impulse propagation. Within 2 weeks after TAC, total and phospho-Cx43 abundance was reduced and incorporation of Cx43 into gap junctional plaques was markedly diminished. These molecular changes were associated with progressive slowing of impulse propagation, as determined by optical mapping with voltage-sensitive dyes. Treatment with the aldosterone receptor antagonist spironolactone, which has been shown to diminish sudden arrhythmic death in clinical trials, was examined for its effects on GJR. We found that spironolactone blunted the development of GJR and also potently reversed established GJR, both at the molecular and functional levels, without diminishing the extent of hypertrophy. These data suggest a potential mechanism for some of the salutary electrophysiological and clinical effects of mineralocorticoid antagonists in myopathic hearts.
authors.affiliation: Leon H. Charney Division of Cardiology, New York University School of Medicine, 522 First Ave, Smilow 801, New York, NY 10016, USA.
authors.forename: Jiaxiang
authors.initials: J
authors.lastname: Qu
authors.forename: Frank M
authors.initials: FM
authors.lastname: Volpicelli
authors.forename: Luis I
authors.initials: LI
authors.lastname: Garcia
authors.forename: Nefthi
authors.initials: N
authors.lastname: Sandeep
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Lucrecia
authors.initials: L
authors.lastname: Márquez-Rosado
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lampe
authors.forename: Glenn I
authors.initials: GI
authors.lastname: Fishman
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology*; D017629:Gap Junctions / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D006329:Heart Conduction System / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000502:physiology; D010766:Phosphorylation; D013148:Spironolactone / Q000494:pharmacology*; D014463:Ultrasonography
chemical_list: D018031:Connexin 43; D004232:Diuretics; D013148:Spironolactone