Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism.
We investigated the effect of the angiotensin type 1 (AT-1) receptor antagonist, irbesartan, on matrix metalloproteinase (MMP) activity and cardiac cytokines in an animal model of diabetic cardiomyopathy. Diabetes was induced in 20 C57/bl6 mice by injection of streptozotocin (STZ). These animals were treated with irbesartan or placebo and were compared with nondiabetic controls. Left ventricular (LV) function was measured by pressure-volume loops with parameters for systolic function (end systolic elastance [Ees]) and diastolic function (cardiac stiffness) 8 weeks after STZ treatment. The cardiac protein content of interleukin (IL)1beta and transforming growth factor (TGF)beta1 were measured by enzyme-linked immunosorbent assay. The total cardiac collagen content and collagen type 1 and 3 were measured by histochemistry, and MMP-2 activity was measured by gelatin zymography. LV dysfunction was documented by impaired Ees and diastolic stiffness in STZ mice compared with controls. This was accompanied by increased TGFbeta, IL1beta, and fibrosis and decreased MMP-2 activity. Treatment with irbesartan attenuated LV dysfunction, IL1beta, TGFbeta, and cardiac fibrosis compared with untreated diabetic animals and normalized MMP activity. These findings present evidence that AT-1 receptor antagonists attenuate cardiac failure by decreasing cardiac inflammation and normalizing MMP activity, leading to normalized cardiac fibrosis in STZ-induced diabetic cardiomyopathy.
Westermann
Dirk
D
Department of Cardiology, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
Rutschow
Susanne
S
Jäger
Sebastian
S
Linderer
Anne
A
Anker
Stefan
S
Riad
Alexander
A
Unger
Thomas
T
Schultheiss
Heinz-Peter
HP
Pauschinger
Matthias
M
Tschöpe
Carsten
C
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000209:etiology*; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D048909:Diabetes Complications / Q000188:drug therapy; D003921:Diabetes Mellitus, Experimental; D006333:Heart Failure; D007249:Inflammation / Q000378:metabolism*; D000077405:Irbesartan; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D024042:Collagen Type I; D024061:Collagen Type III; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D020782:Matrix Metalloproteinases; D000077405:Irbesartan