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Contributions of Inflammation and Cardiac Matrix Metalloproteinase Activity to Cardiac Failure in Diabetic Cardiomyopathy

The Role of Angiotensin Type 1 Receptor Antagonism

¹ Department of Cardiology and Pneumology, Benjamin Franklin Campus, Charité Universitätsmedizin Berlin, Berlin, Germany
² Center for Cardiovascular Research/Institute of Pharmacology, Charité Universitätsmedizin Berlin, Berlin, Germany

Address correspondence and reprint requests to Carsten Tschöpe, MD, Department of Cardiology, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail: ctschoepe{at}yahoo.com

Abbreviations: ANGII, angiotensin II; ARB, angiotensin receptor blocker; AT-1, angiotensin type 1; dP/dt max, contractility; dP/dt min, relaxation; Ees, end systolic elastance; IL, interleukin; LV, left ventricular; LVEDP, LV end diastolic pressure; MMP, matrix metalloproteinase; STZ, streptozotocin; TGF, transforming growth factor

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)1ß and transforming growth factor (TGF)ß1 were measured by enzyme-linked immunosorbent assay. The total cardiac collagen content and collagen type 1 and 3 were measured by histochemestry, 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 TGFß, IL1ß, and fibrosis and decreased MMP-2 activity. Treatment with irbesartan attenuated LV dysfunction, IL1ß, TGFß, 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.

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