title: Aliskiren and Valsartan reduce myocardial AT1 receptor expression and limit myocardial infarct size in diabetic mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Db/Db mice, fed Western Diet, received 15-day pretreatment with: 1) vehicle; 2) AL 25 mg/kg/d; 3) AL 50 mg/kg/d; 4) VA 8 mg/kg/d; 5) VA 16 mg/kg/d; 6) AL 25+VA 16 mg/kg/d; or 7) AL 50+VA 16 mg/kg/d. Mice underwent 30 min coronary artery occlusion and 24 h reperfusion. Area at risk (AR) was assessed by blue dye and IS by TTC staining. Protein expression was assessed by immunobloting.
  
  
  RESULTS
  IS in the control group was 42.9 ± 2.1% of the AR. AL at 25 (21.9 ± 2.9%) and 50 mg/kg/d (15.5 ± 1.3%) reduced IS. VA at 16 mg/kg/d (18.8 ± 1.2%), but not at 8 mg/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.
  
  
  CONCLUSIONS
  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 (16 mg/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.
authors: The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, USA. yumye@utmb.edu
authors: Yumei
authors: Y
authors: Ye
authors: Jinqiao
authors: J
authors: Qian
authors: Alexander C
authors: AC
authors: Castillo
authors: Jose Regino
authors: JR
authors: Perez-Polo
authors: Yochai
authors: Y
authors: Birnbaum
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004359:Drug Therapy, Combination; D005650:Fumarates / Q000008:administration & dosage / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis*; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D005650:Fumarates; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014633:Valine; D000068756:Valsartan; D000092502:Renin Inhibitors; C446481:aliskiren