Silencing of the Na+/H+ exchanger 1(NHE-1) prevents cardiac structural and functional remodeling induced by angiotensin II

Abstract

Chronic activation of the renin angiotensin system (RAS) favors several cardiac diseases, among which myocardial hypertrophy occupies an outstanding place. In this context, the hyperactivity of the cardiac Na+/H+ (NHE-1) exchanger plays a key role. The pathologic remodeling of the myocardium constitutes an independent risk factor for morbidity and mortality with continuously increasing healthcare cost. Therefore, the development of better therapeutic strategies emerges as highly mandatory. Our goal was to prevent angiotensin II (ANGII)-induced cardiac hypertrophy by NHE-1 gene silencing in Wistar rats. The intramyocardial injection of a lentivirus coding a specific small interference RNA (l-shNHE1) significantly reduced NHE-1 expression exclusively in the heart (~ 50 %) and prevented cardiac remodeling in rats exposed to chronic infusion of ANG II (heart weigh/tibia length: 24,03 ± 0,7915 mg/mm vs 28,45 ± 0,9779 mg/mm and collagen volume fraction 2,526 ± 0,5003 vs 5,982 ± 1,043 in l-shNHE1 + ANGII and ANGII, respectively).Interestingly, this was accompanied by an improvement in cardiac function determined by echocardiography even though blood pressure remained elevated (Fractional shortening 0,5960 ± 0,4228 vs -0,9567± 0,06888 and blood pressure at the end of ANGII treatment 141,2 ± 6,117 mm Hg vs 134,1 ± 6,723 mm Hg ; in l-shNHE1 + ANGII and ANGII, respectively). ANGII infusion increased myocardial NADPH oxidase activity but the l-shNHE1 injection prevented oxidative stressas revealed by the normalization of lipid peroxidation (T-BARS 12,40 ± 2,887.vs 23,05 ± 1,537 in lshNHE1 + ANGII and ANGII, respectively). These results allow as to propose the partial silencing of the cardiac NHE-1 through lentiviralinjection as a promising tool in the prevention of ANGII-induced cardiac hypertrophy.