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Remodeling of Gap Junctional Coupling in Hypertrophied Right Ventricles of Rats With Monocrotaline-Induced Pulmonary Hypertension

The present study investigates the remodeling of gap junctional organization in relation to changes in anisotropic conduction properties in hypertrophied right ventricles (RVs) of rats with monocrotaline (MCT)-induced pulmonary hypertension. In contrast to controls that showed immunolocalization of connexin43 (Cx43) labeling largely confined to the intercalated disks, RV myocytes from MCT-treated rats showed dispersion of Cx43 labeling over the entire cell surface. The disorganization of Cx43 labeling became more pronounced with the progression of hypertrophy. Desmoplakin remained localized to the intercalated disks, as in controls. In RV tissues, the proportion of Cx43 label at the intercalated disk progressively decreased. Quantitative analysis of en face views of intercalated disks revealed a significant decrease in the disk gap junctional density in RV tissues of MCT-treated rats (control, 0.18 versus MCT-treated, 0.14 at 2 weeks; control, 0.16 versus MCT-treated, 0.11 at 4 weeks). Conduction velocity in RVs parallel to the fiber orientation was significantly lower (30.2% [n=9]) in MCT-treated rats at 4 weeks than in control rats, whereas there was no significant difference observed in the conduction velocity across the fiber orientation between control and MCT-treated rats. The anisotropic ratio of MCT-treated rats (1.38+/-0.10) was significantly lower than that of control rats (1.98+/-0.12). These results suggest that RV hypertrophy induced by pressure overload is associated with both disorganization of gap junction distribution and alteration of anisotropic conduction properties.

Dephosphorylation of Connexin43 Associated with Ventricular Hypertrophy

Altered expression and distribution of gap junctions in hypertrophied hearts may provide a potential substrate for abnormal conduction. We investigated changes of phosphorylation state of connexin43 (Cx43) in hypertrophied rat right ventricles secondary to pulmonary hypertension induced by monocrotaline (MCT) using western blot analysis. In normal right ventricular myocardium, most of Cx43 was phosphorylated. In hypertrophied ventricles of MCT-treated rats, the non-phosphorylated isoform of Cx43 increased and the phosphorylated isoform of Cx43 decreased with no significant a change in the total amount of Cx43 protein. These results suggest that dephosphorylation of Cx43 in MCT-induced right ventricular hypertrophy may be involved in gap junction disorganization.