Aliskiren and Valsartan reduce myocardial AT1 receptor expression and limit myocardial infarct size in diabetic mice

Yumei Ye, Jinqiao Qian, Alexander C. Castillo, Jose Regino Perez-Polo, Yochai Birnbaum

Research output: Contribution to journalArticle

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Abstract

Purpose: 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.

Original languageEnglish (US)
Pages (from-to)505-515
Number of pages11
JournalCardiovascular Drugs and Therapy
Volume25
Issue number6
DOIs
StatePublished - Dec 2011

Fingerprint

Valsartan
Myocardial Infarction
Type 2 Diabetes Mellitus
Phosphorylation
aliskiren
Angiotensin Receptor Antagonists
Coronary Occlusion

Keywords

  • Angiotensin receptor blocker
  • Direct renin inhibitor
  • Infarct size
  • Ischemia-reperfusion injury
  • Sirt1
  • Type-2 diabetes mellitus

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

Aliskiren and Valsartan reduce myocardial AT1 receptor expression and limit myocardial infarct size in diabetic mice. / Ye, Yumei; Qian, Jinqiao; Castillo, Alexander C.; Perez-Polo, Jose Regino; Birnbaum, Yochai.

In: Cardiovascular Drugs and Therapy, Vol. 25, No. 6, 12.2011, p. 505-515.

Research output: Contribution to journalArticle

Ye, Yumei ; Qian, Jinqiao ; Castillo, Alexander C. ; Perez-Polo, Jose Regino ; Birnbaum, Yochai. / Aliskiren and Valsartan reduce myocardial AT1 receptor expression and limit myocardial infarct size in diabetic mice. In: Cardiovascular Drugs and Therapy. 2011 ; Vol. 25, No. 6. pp. 505-515.
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abstract = "Purpose: 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.",
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T1 - Aliskiren and Valsartan reduce myocardial AT1 receptor expression and limit myocardial infarct size in diabetic mice

AU - Ye, Yumei

AU - Qian, Jinqiao

AU - Castillo, Alexander C.

AU - Perez-Polo, Jose Regino

AU - Birnbaum, Yochai

PY - 2011/12

Y1 - 2011/12

N2 - Purpose: 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.

AB - Purpose: 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.

KW - Angiotensin receptor blocker

KW - Direct renin inhibitor

KW - Infarct size

KW - Ischemia-reperfusion injury

KW - Sirt1

KW - Type-2 diabetes mellitus

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