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Gene deletion of the kinin receptor B1 attenuates cardiac inflammation and fibrosis during the development of experimental diabetic cardiomyopathy.

Westermann D, Walther T, Savvatis K, Escher F, Sobirey M, Riad A, Bader M, Schultheiss HP, Tschöpe C - Diabetes (2009)

Bottom Line: The underlying pathology of this disease is still under discussion.Furthermore, the left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes.This was associated with a decreased activation state of the mitogen-activated protein kinase p38, less oxidative stress, as well as normalized cardiac inflammation, shown by fewer invading cells and no increase in matrix metalloproteinase-9 as well as the chemokine CXCL-5.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology and Pneumology, Charité -Universitä tsmedizinBerlin, Campus Benjamin Franklin, Berlin, Germany.

ABSTRACT

Objective: Diabetic cardiomyopathy is associated with increased mortality in patients with diabetes. The underlying pathology of this disease is still under discussion. We studied the role of the kinin B1 receptor on the development of experimental diabetic cardiomyopathy.

Research design and methods: We utilized B1 receptor knockout mice and investigated cardiac inflammation, fibrosis, and oxidative stress after induction of streptozotocin (STZ)-induced diabetes. Furthermore, the left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes.

Results: B1 receptor knockout mice showed an attenuation of diabetic cardiomyopathy with improved systolic and diastolic function in comparison with diabetic control mice. This was associated with a decreased activation state of the mitogen-activated protein kinase p38, less oxidative stress, as well as normalized cardiac inflammation, shown by fewer invading cells and no increase in matrix metalloproteinase-9 as well as the chemokine CXCL-5. Furthermore, the profibrotic connective tissue growth factor was normalized, leading to a reduction in cardiac fibrosis despite severe hyperglycemia in mice lacking the B1 receptor.

Conclusions: These findings suggest that the B1 receptor is detrimental in diabetic cardiomyopathy in that it mediates inflammatory and fibrotic processes. These insights might have useful implications on future studies utilizing B1 receptor antagonists for treatment of human diabetic cardiomyopathy.

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Related in: MedlinePlus

mRNA levels of cardiac cytokines in control mice (B1R+/+) or mice lacking the B1R (B1R−/−) under basal conditions and 8 weeks after induction of STZ-induced diabetes with increased levels of IL-1β, IL-6, and TNF-α in STZ measured by real-time RT-PCR. Moreover, the figure shows mRNA levels of the chemokine CXCL-5 levels as well as mRNA levels of the B1R and B2R. *P < 0.05 vs. B1R+/+ and B1R−/− STZ. #P < 0.05 vs. B1R+/+.
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Figure 2: mRNA levels of cardiac cytokines in control mice (B1R+/+) or mice lacking the B1R (B1R−/−) under basal conditions and 8 weeks after induction of STZ-induced diabetes with increased levels of IL-1β, IL-6, and TNF-α in STZ measured by real-time RT-PCR. Moreover, the figure shows mRNA levels of the chemokine CXCL-5 levels as well as mRNA levels of the B1R and B2R. *P < 0.05 vs. B1R+/+ and B1R−/− STZ. #P < 0.05 vs. B1R+/+.

Mentions: In the myocardium of the diabetic mice, the mRNA abundance of the proinflammatory cytokines IL-1β, IL-6, and TNF-α as well as the chemokine CXCL-5 were significantly increased by B1R+/+-STZ compared with controls (Fig. 2). This was associated with increased numbers of CD3+, CD11b+, CD45+, and CD68+cells (Fig. 3) and the protein abundance of MMP-9 (Fig. 4). This upregulation was prevented by B1R−/−-STZ, resulting in normalized levels compared with controls. Moreover, a major part of TNF-α is produced by inflammatory cells (CD68) (Fig. 5). The abundance of nitrotyrosine and myeloperoxidase was increased in the cardiac tissue of the STZ group, as an indicator of increased oxidative stress (Fig. 4). The lack of the B1R reduced this increased expression of nitrotyrosine and myeloperoxidase in comparison with STZ, despite severe hyperglycemia when B1R−/−-STZ was compared with B1R+/+-STZ (Fig. 4).


Gene deletion of the kinin receptor B1 attenuates cardiac inflammation and fibrosis during the development of experimental diabetic cardiomyopathy.

Westermann D, Walther T, Savvatis K, Escher F, Sobirey M, Riad A, Bader M, Schultheiss HP, Tschöpe C - Diabetes (2009)

mRNA levels of cardiac cytokines in control mice (B1R+/+) or mice lacking the B1R (B1R−/−) under basal conditions and 8 weeks after induction of STZ-induced diabetes with increased levels of IL-1β, IL-6, and TNF-α in STZ measured by real-time RT-PCR. Moreover, the figure shows mRNA levels of the chemokine CXCL-5 levels as well as mRNA levels of the B1R and B2R. *P < 0.05 vs. B1R+/+ and B1R−/− STZ. #P < 0.05 vs. B1R+/+.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682670&req=5

Figure 2: mRNA levels of cardiac cytokines in control mice (B1R+/+) or mice lacking the B1R (B1R−/−) under basal conditions and 8 weeks after induction of STZ-induced diabetes with increased levels of IL-1β, IL-6, and TNF-α in STZ measured by real-time RT-PCR. Moreover, the figure shows mRNA levels of the chemokine CXCL-5 levels as well as mRNA levels of the B1R and B2R. *P < 0.05 vs. B1R+/+ and B1R−/− STZ. #P < 0.05 vs. B1R+/+.
Mentions: In the myocardium of the diabetic mice, the mRNA abundance of the proinflammatory cytokines IL-1β, IL-6, and TNF-α as well as the chemokine CXCL-5 were significantly increased by B1R+/+-STZ compared with controls (Fig. 2). This was associated with increased numbers of CD3+, CD11b+, CD45+, and CD68+cells (Fig. 3) and the protein abundance of MMP-9 (Fig. 4). This upregulation was prevented by B1R−/−-STZ, resulting in normalized levels compared with controls. Moreover, a major part of TNF-α is produced by inflammatory cells (CD68) (Fig. 5). The abundance of nitrotyrosine and myeloperoxidase was increased in the cardiac tissue of the STZ group, as an indicator of increased oxidative stress (Fig. 4). The lack of the B1R reduced this increased expression of nitrotyrosine and myeloperoxidase in comparison with STZ, despite severe hyperglycemia when B1R−/−-STZ was compared with B1R+/+-STZ (Fig. 4).

Bottom Line: The underlying pathology of this disease is still under discussion.Furthermore, the left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes.This was associated with a decreased activation state of the mitogen-activated protein kinase p38, less oxidative stress, as well as normalized cardiac inflammation, shown by fewer invading cells and no increase in matrix metalloproteinase-9 as well as the chemokine CXCL-5.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology and Pneumology, Charité -Universitä tsmedizinBerlin, Campus Benjamin Franklin, Berlin, Germany.

ABSTRACT

Objective: Diabetic cardiomyopathy is associated with increased mortality in patients with diabetes. The underlying pathology of this disease is still under discussion. We studied the role of the kinin B1 receptor on the development of experimental diabetic cardiomyopathy.

Research design and methods: We utilized B1 receptor knockout mice and investigated cardiac inflammation, fibrosis, and oxidative stress after induction of streptozotocin (STZ)-induced diabetes. Furthermore, the left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes.

Results: B1 receptor knockout mice showed an attenuation of diabetic cardiomyopathy with improved systolic and diastolic function in comparison with diabetic control mice. This was associated with a decreased activation state of the mitogen-activated protein kinase p38, less oxidative stress, as well as normalized cardiac inflammation, shown by fewer invading cells and no increase in matrix metalloproteinase-9 as well as the chemokine CXCL-5. Furthermore, the profibrotic connective tissue growth factor was normalized, leading to a reduction in cardiac fibrosis despite severe hyperglycemia in mice lacking the B1 receptor.

Conclusions: These findings suggest that the B1 receptor is detrimental in diabetic cardiomyopathy in that it mediates inflammatory and fibrotic processes. These insights might have useful implications on future studies utilizing B1 receptor antagonists for treatment of human diabetic cardiomyopathy.

Show MeSH
Related in: MedlinePlus