Regulation of intercellular coupling in acute and chronic heart disease

Abstract

Effective pump function of the heart depends on the precise control of spatial and temporal patterns of electrical activation. Accordingly, the distribution and function of gap junction channels are important determinants of the conduction properties of myocardium and undoubtedly play other roles in intercellular communication crucial to normal cardiac function. Recent advances have begun to elucidate mechanisms by which the heart regulates intercellular electrical coupling at gap junctions in response to stress or injury. Although responses to increased load or injury are generally adaptive in nature, remodeling of intercellular junctions under conditions of severe stress creates anatomic substrates conducive to the development of lethal ventricular arrhythmias. Potential mechanisms controlling the level of intercellular communication in the heart include regulation of connexin turnover dynamics and phosphorylation. Correspondence

Sodium Hydrogen Exchange 1 (NHE-1) Regulates Connexin 43 Expression in Cardiomyocytes via Reverse Mode Sodium Calcium Exchange and c-Jun NH2-Terminal Kinase-Dependent Pathways

“…The ability of NHE-1 inhibition to augment the increase in Cx43 expression, while at the same time abrogating the hypertrophic response to phenylephrine, shows that the elevation in Cx43 expression can be dissociated from hypertrophy per se. In addition, this finding is compatible with the notion of a beneficial effect of NHE-1 inhibition in attenuating the hypertrophic and remodeling responses to pathological insult, given that early up-regulation of Cx43 expression is meant to provide the heart with improved electrical conduction and cardiac function during pathological conditions (Saffitz, 2000). Thus, in addition to the established salutary effects of NHE-1 inhibition in attenuating hypertrophy and remodeling (reviewed in Cingolani and Ennis, 2007;Karmazyn et al, 2008), these results suggest that additional benefit may lie in the ability of these agents to increase Cx43 expression, thus potentially improving cardiac functioning in parallel with reduced hypertrophy.…”

c-Jun N-Terminal Kinase Activation Mediates Downregulation of Connexin43 in Cardiomyocytes

“…Therefore, JNK is most likely involved in Cx43 regulation at the posttranscriptional level. Although the regulation of both synthesis and degradation probably plays a role in Cx43 homeostasis, 42 further studies will be needed to establish the specific mechanisms of JNK-mediated Cx43 downregulation, includ- ing changes in Cx43 protein synthesis, degradation, and membrane assembly.…”

Gap junctions: structure and function (Review)

“…In the heart and cardiovascular system, Cx40, 43 and 45 are located at gap junctions that underpin intercellular current flow and ensure synchronous contraction of myocytes (Saffitz 2000). Conduction defects cause fatal ventricular arrhythmias and connexin abnormalities are present in diseased hearts.…”