Impact of volume overload on cardiac connexin-43 and extracellular matrix of normotensive and hypertensive Ren-2 transgenic rats: Effects of treatment with Trandolapril and Losartan

Abstract

Abstract Heart failure (HF) is life-threatening disease due to electro-mechanical dysfunction associated with hemodynamic overload, while alterations of extracellular matrix (ECM) along with perturbed connexin-43 (Cx43) might be key factors involved. We aimed to explore an impact of volume overload due to aorto-caval fistula (ACF) on Cx43 and ECM as well as effect of renin-angiotensin blockade. Hypertensive Ren-2 transgenic rats (TGR) and normotensive Hannover Sprague–Dawley rats (HSD) that underwent ACF were treated for 15-weeks with Trandolapril or Losartan. Blood serum and heart tissue samples of the right (RV) and left ventricles (LV) were used for analyses. ACF-HF increased RV and LV mass in HSD and to lesser extent in TGR, while treatment attenuated it and normalized serum ANP and TBARS. Cx43 protein and its ser368 variant along PKCε were lower in TGR vs HSD and suppressed in both rat strains due to ACF but prevented more by trandolapril. Pro-hypertrophic PKCδ, collagen I and hydroxyproline were elevated in TGR and increased due to ACF in both rat strains. While Smad2/3 and MMP2 levels were lower in TGR vs HSD and reduced due to ACF in both strains. Findings point out the strain-related differences in response to volume overload. While disorders of Cx43 and ECM signalling may contribute not only to HF but also to malignant arrhythmia risk. There is benefit of treatment with trandolapril and losartan indicating their pleitropic antiarrhytmic potential. It may provide novel input to therapy.