Connexin 43 downregulation and dephosphorylation in nonischemic heart failure is associated with enhanced colocalized protein phosphatase type 2A.
In nonischemic heart failure (HF), ventricular tachycardia initiates by a nonreentrant mechanism, but there is altered conduction (that could lead to re-entry) that could arise from changes in gap junctional proteins, especially connexin43 (Cx43). We studied Cx43 expression and phosphorylation state in the left ventricle (LV) from an arrhythmogenic rabbit model of nonischemic HF and from patients with HF attributable to idiopathic dilated cardiomyopathy. We also investigated the role of protein phosphatases that dephosphorylate Cx43--PP1 and PP2A. In HF rabbit LV, Cx43 mRNA and total protein were decreased by 29% and 34%, respectively (P<0.05 and P<0.001). In controls, Cx43 was primarily in the phosphorylated state, but with HF there was a 64% increase in nonphosphorylated Cx43 (Cx43-NP, normalized to total Cx43; P<0.05). Similar results were noted in HF rabbit myocytes (P<0.05) and in human idiopathic dilated cardiomyopathy LV (P<0.05). We found that PP1 and PP2A colocalized with Cx43 in rabbit LV. With HF, the level of colocalized PP2A increased >2.5-fold (P<0.002), whereas colocalized PP1 was unchanged. We also found intercellular coupling (assessed by Lucifer Yellow dye transfer) was markedly reduced in HF. However, okadaic acid (10 nmol/L) reduced the amount of Cx43-NP and significantly improved cell coupling in HF. Thus, in nonischemic HF in rabbits and humans, there is a decrease in both Cx43 expression and phosphorylation that contributes to uncoupling. Increased levels of PP2A that colocalize with Cx43 can underlie enhanced levels of Cx43-NP in HF. Modulation of Cx43 phosphorylation may be a potential therapeutic target to improve conduction in HF.
Ai
Xun
X
Department of Medicine, University of Illinois at Chicago, IL 60612, USA.
Pogwizd
Steven M
SM
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000150:complications; D004396:Coloring Agents / Q000493:pharmacokinetics; D018031:Connexin 43 / Q000378:metabolism*; D017629:Gap Junctions / Q000502:physiology*; D005786:Gene Expression Regulation; D006329:Heart Conduction System / Q000503:physiopathology*; D006333:Heart Failure / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000493:pharmacokinetics; D032383:Myocytes, Cardiac / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000032:analysis / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology
D004396:Coloring Agents; D018031:Connexin 43; D007546:Isoquinolines; D012333:RNA, Messenger; C017475:lucifer yellow; D010749:Phosphoprotein Phosphatases