Aliskiren and Valsartan Reduce Myocardial AT1 Receptor Expression and Limit Myocardial Infarct Size in Diabetic Mice

Abstract

We assessed the ability of Aliskiren (AL), a direct renin inhibitor, and Valsartan (VA), an angiotensin receptor blocker, to limit myocardial infarct size (IS) in mice with type-2 diabetes mellitus. Db/Db mice, fed Western Diet, received 15-day pretreatment with: 1) vehicle; 2) AL 25mg/kg/d; 3) AL 50mg/kg/d; 4) VA 8mg/kg/d; 5) VA 16mg/kg/d; 6) AL 25+VA 16mg/kg/d; or 7) AL 50+VA 16mg/kg/d. Mice underwent 30min coronary artery occlusion and 24h reperfusion. Area at risk (AR) was assessed by blue dye and IS by TTC staining. Protein expression was assessed by immunobloting. IS in the control group was 42.9 ± 2.1% of the AR. AL at 25 (21.9 ± 2.9%) and 50mg/kg/d (15.5 ± 1.3%) reduced IS. VA at 16mg/kg/d (18.8 ± 1.2%), but not at 8mg/kg/d (35.2 ± 4.0%), limited IS. IS was the smallest in the AL50+VA16 group (6.3 ± 0.9%). Both AL and VA reduced myocardial AT1R levels, without affecting AT2R levels, and increased the expression of Sirt1 and PGC-1α with increased phosphorylation of Akt and eNOS. AL, dose dependently limited myocardial IS in mice with type-2 diabetes mellitus. At doses shown to limit IS in non-diabetic animals, VA failed to reduce IS in Db/Db mice. However, at higher dose (16mg/kg/d), VA reduced IS. Both drugs reduced the expression of AT1R and increased myocardial levels of the longevity genes Sirt1 and PGC-1α along with increased Akt and eNOS phosphorylation.