CCN5 Overexpression Triggers Early Amplification Followed by Regression of Electrical Remodeling in a Pressure Overload Rat Model

Abstract

The matricellular proteins CCN2 & CCN5 play opposing roles in pressure overload hypertrophy (PoH). While CCN2 promotes adverse remodeling, CCN5 suppresses fibrosis and therefore may be an important therapeutic target. Since arrhythmias are prevalent during early stages of PoH, we investigated the electrophysiological (EP) effects of CCN5 gene transfer (GT) in a rat model. We hypothesized that CCN5 GT prevents electromechanical dysfunction in PoH. Methods: 4 wk old rats underwent aortic constriction and were randomized to receive AAV9 CCN5 or an empty vector (E) 3 wks later. In vivo hemodynamic analysis followed by ex vivo EP measurements using high resolution optical action potential (AP) mapping were performed at 9 or 21 wks of PoH. Results: CCN5 GT did not prevent but rather amplified early electromechanical remodeling as fractional shortening was significantly reduced, AP duration prolonged, and conduction velocity (CV) impaired in AAV9 CCN5 compared to AAV9 E hearts (Fig, top). Remarkably EP remodeling in AAV9 CCN5 hearts was largely reversed by 21 wks of PoH (Fig, top). To probe the basis of these unexpected findings, we tested whether CCN5 GT alters the EP substrate in normal (fibrosis free) hearts. Indeed AAV9 CCN5 GT caused significant CV slowing, consistent with a potent effect on excitability that was independent of fibrosis (Fig, bottom). Conclusions: CCN5 GT alters myocardial conduction by directly modulating gap junction and/or Na channel function. EP remodeling is amplified during early PoH but undergoes regression at later stages possibly through reversal of fibrosis. CCN5 modulates the EP substrate via fibrosis dependent (late) and independent (early) effects.