TY - JOUR
T1 - Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy
T2 - The role of angiotensin type 1 receptor antagonism
AU - Westermann, Dirk
AU - Rutschow, Susanne
AU - Jäger, Sebastian
AU - Linderer, Anne
AU - Anker, Stefan
AU - Riad, Alexander
AU - Unger, Thomas
AU - Schultheiss, Heinz Peter
AU - Pauschinger, Matthias
AU - Tschöpe, Carsten
PY - 2007/3
Y1 - 2007/3
N2 - 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)1β and transforming growth factor (TGF)β1 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 TGFβ, IL1β, and fibrosis and decreased MMP-2 activity. Treatment with irbesartan attenuated LV dysfunction, IL1β, TGFβ, 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.
AB - 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)1β and transforming growth factor (TGF)β1 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 TGFβ, IL1β, and fibrosis and decreased MMP-2 activity. Treatment with irbesartan attenuated LV dysfunction, IL1β, TGFβ, 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.
UR - http://www.scopus.com/inward/record.url?scp=33847342561&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33847342561&partnerID=8YFLogxK
U2 - 10.2337/db06-1163
DO - 10.2337/db06-1163
M3 - Article
C2 - 17327431
AN - SCOPUS:33847342561
VL - 56
SP - 641
EP - 646
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 3
ER -