Gap Junction Remodeling and Spironolactone-Dependent Reverse Remodeling in the Hypertrophied Heart

Abstract

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.

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…The spatial dispersion of QT interval is restored, whereas the ST segment depression and action potential propagation and conduction velocity are considerably improved (De Mello, 2006). Similarly, spironolactone treatment prevents gap junction remodeling and restores the decreased transverse conduction velocity in a thoracic aortic constriction model (Qu et al, 2009). Likewise, eplerenone reduces fibrosis-related arrhythmias in aged mice (Stein et al, 2010).…”

Reduced Cx43 Expression Triggers Increased Fibrosis Due to Enhanced Fibroblast Activity

“…This viewpoint is further supported by the finding that our aged 22-month-old Cx43 fl/fl control mice have lower levels of Cx43 compared with 5-month-old Cx43 fl/fl mice, resulting in increased levels of fibrosis in the aged mice (data not shown). Also, researchers have shown that long-term inhibition of the renin-angiotensin-aldosterone system of aging mice, 2 cardiomyopathic hamsters, 30 and TAC mice 31 prevents gap junction remodeling and leads to reduced levels of fibrosis. The general mechanistic view is that enhanced interstitial fibrosis leads to separation of the myocardial fibers with subsequent reduction of gap junction plaques.…”

Longitudinal arrhythmogenic remodelling in a mouse model of longstanding pressure overload

“…6 Cardiac systolic function was well compensated for the first four weeks after TAC, but gradually deteriorated thereafter, which is comparable with other studies in which decompensation also occurred after four to five weeks. [7][8][9] Systolic function was lower in TAC mice with arrhythmias (TAC+), compared with TAC mice without arrhythmias (TAC-), albeit not significant (35.0±2.7% vs. 42.2±3.6% in TAC-and TAC+, respectively; p=0.14). Interestingly, lung weight was significantly higher in TAC+, suggesting that the amount of backward failure may play a proarrhythmic role (0.261±0.043g vs. 0.178±0.005g in TAC-and TAC+, respectively).…”