Chronic effects of endothelin‐1 and angiotensin‐II on gap junctions and intercellular communication in cardiac cells

Abstract

Endothelin-1 (ET-1) and angiotensin-II (AT-II) participate in the pathophysiology of cardiovascular diseases. Regulation of gap junctional intercellular communication may influence heart function and its response to cardiac injury. In this study, we examined the effects of ET-1 and AT-II on connexin43 (Cx43) and connexin40 (Cx40) in cultured neonatal rat ventricular cardiomyocytes (NRCs) and the role of mitogen-activated protein kinase signaling in the ET-1- and AT-II-induced responses. NRCs were incubated for 24 h with either ET-1 or AT-II (each at concentrations ranging from 10 to 1000 nM), and Cx43 expression and phosphorylation increased with increasing concentrations of both. ET-1 effects were significantly blocked by ETA (BQ123), but not by ETB (BQ788), receptor antagonists. AT-II-induced Cx43 induction could be completely inhibited by the AT1 receptor antagonist losartan. In contrast to Cx43, Cx40 expression did not change in either ET-1- or in AT-II-treated NRCs. Thus, these two connexins were differentially regulated. ET-1 and AT-II increased the gap junctional conductance between the cardiomyocytes in culture as measured using a dual-cell voltage clamp. Mitogen-activated protein kinase inhibition revealed that ERK1/2 was critical for up-regulation of Cx43 in response to ET-1, whereas both ERK and p38 signal pathways were involved in the regulation of Cx43 by AT-II. Thus, stimulation of the ERK and p38 signal pathways via ETA and AT1 receptors may partcipate in the regulation of cardiac gap junctions under (patho)physiological conditions.

Effects of angiotensin II on connexin 43 of VSMCs in arteriosclerosis

“…Study also showed that AT 1 antagonist could inhibit the upregulation of Cx43 in rat ventricular myocytes induced by periodic mechanical stretching (Shyu et al, 2001), suggesting that the tissues RAS system plays an important role in the remodelling of GJ in ventricular myocytes under pathological conditions (Emdad et al, 2001). Polontchouk et al(2002) reported that after administrating Ang II to neonatal rat myocardial cells for 24 h, Cx43 increased by approximately 50% and led to multiplicative electric-coupling.…”

Chronic blockade of angiotensin II AT1-receptors increased cell-to-cell communication, reduced fibrosis and improved impulse propagation in the failing heart

“…22,23 Although the reason for this difference is not known, neonatal cardiac cells seem to be quite different from adult differentiated myocytes. Indeed, Saris et al 24 were unable to detect Ang II generation in neonatal cardiomyocytes after addition of prorenin to the medium.…”

Reversible atrial gap junction remodeling during hypoxia/reoxygenation and ischemia: a possible arrhythmogenic substrate for atrial fibrillation

“…In this study, we failed to find changes in atrial connexin expression after treatment with Ang II, while, in ventricular myocytes, Ang II increased Cx43 expression level (Polontchouk et al 2002). Thus, the therapeutic effects of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on AF could be mediated by molecular pathways not involving connexin expression.…”