Angiotensin II type 1 receptor blocker attenuates myocardial remodeling and preserves diastolic function in diabetic heart.
Blockade of the renin-angiotensin system reduces cardiovascular morbidity and mortality in diabetic patients. Angiotensin II (Ang II) plays an important role in the structural and functional abnormalities of the diabetic heart. We investigated whether or not Ang II type 1 receptor blocker (ARB) could attenuate left ventricular (LV) remodeling in male mice with diabetes mellitus (DM) induced by the injection of streptozotocin (200 mg/kg, i.p.). Diabetic mice were treated with candesartan (1 mg/kg/day; DM+Candesartan, n=7) or vehicle (DM+Vehicle, n=7) for 8 weeks. Heart rate and aortic blood pressure were comparable between the groups. Normal systolic function was preserved in diabetic mice. In contrast, diastolic function was impaired in DM+Vehicle and was improved in DM+Candesartan, as assessed by the deceleration time of the peak velocity of transmitral diastolic flow (40.3+/-0.3 vs. 37.3+/-0.5 ms, p<0.01) and the time needed for relaxation of 50% maximal LV pressure to baseline value (tau; 10.6+/-0.7 vs. 8.7+/-0.6 ms, p<0.05) without significant changes in heart rate and aortic blood pressure. Improvement of LV diastolic function was accompanied by the attenuation of myocyte hypertrophy, interstitial fibrosis and apoptosis in association with the expression of connective tissue growth factor (CTGF) and myocardial oxidative stress. Moreover, candesartan directly inhibited Ang II-mediated induction of CTGF in cultured cardiac fibroblasts. ARB might be beneficial to prevent cardiac abnormalities in DM.
Tsutsui
Hiroyuki
H
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan. htsutsui@med.hokudai.ac.jp
Matsushima
Shouji
S
Kinugawa
Shintaro
S
Ide
Tomomi
T
Inoue
Naoki
N
Ohta
Yukihiro
Y
Yokota
Takashi
T
Hamaguchi
Sanae
S
Sunagawa
Kenji
K
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001786:Blood Glucose; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D048909:Diabetes Complications / Q000188:drug therapy*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003971:Diastole / Q000187:drug effects; D004452:Echocardiography; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology; D006339:Heart Rate / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D032386:Myoblasts, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013777:Tetrazoles / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D001786:Blood Glucose; C526318:CCN2 protein, mouse; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D020782:Matrix Metalloproteinases; C081643:candesartan