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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

A: Immunofluorescent stainings of cardiac tissue of B1R+/+-STZ and B1R−/−-STZ showing protein levels of TAK-1 binding protein (TAB-1) and α-sacromeric actin as well as DAPI (for cell nuclei). This demonstrates a reduced protein content of TAB-1 in B1R−/−-STZ. B: Quantification of protein levels of the MAPK p38 and its phosphorylated form as well as TAB-1 showing a normalization of the p38 activation and the TAB-1 protein content in B1R−/−-STZ compared with B1R+/+-STZ. *P < 0.05 vs. B1R−/−-STZ. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 6: A: Immunofluorescent stainings of cardiac tissue of B1R+/+-STZ and B1R−/−-STZ showing protein levels of TAK-1 binding protein (TAB-1) and α-sacromeric actin as well as DAPI (for cell nuclei). This demonstrates a reduced protein content of TAB-1 in B1R−/−-STZ. B: Quantification of protein levels of the MAPK p38 and its phosphorylated form as well as TAB-1 showing a normalization of the p38 activation and the TAB-1 protein content in B1R−/−-STZ compared with B1R+/+-STZ. *P < 0.05 vs. B1R−/−-STZ. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Protein levels of endothelial nitric oxide synthase levels (eNOS) were downregulated in both diabetic groups. Nevertheless, the mRNA content was only downregulated significantly in the the B1R+/+-STZ but not in the B1R−/−-STZ mice (Fig. 4). Furthermore, the phosphorylation state of the MAPK p38, known to contribute to tissue inflammation, was increased in STZ mice compared with controls, again an effect that was reduced in B1R−/−-STZ mice when compared with controls. Moreover, TAB-1 protein was significantly inreased in diabetic wild-type compared with B1R−/−-STZ mice (Fig. 6).


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)

A: Immunofluorescent stainings of cardiac tissue of B1R+/+-STZ and B1R−/−-STZ showing protein levels of TAK-1 binding protein (TAB-1) and α-sacromeric actin as well as DAPI (for cell nuclei). This demonstrates a reduced protein content of TAB-1 in B1R−/−-STZ. B: Quantification of protein levels of the MAPK p38 and its phosphorylated form as well as TAB-1 showing a normalization of the p38 activation and the TAB-1 protein content in B1R−/−-STZ compared with B1R+/+-STZ. *P < 0.05 vs. B1R−/−-STZ. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy
Related In: Results  -  Collection

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

Figure 6: A: Immunofluorescent stainings of cardiac tissue of B1R+/+-STZ and B1R−/−-STZ showing protein levels of TAK-1 binding protein (TAB-1) and α-sacromeric actin as well as DAPI (for cell nuclei). This demonstrates a reduced protein content of TAB-1 in B1R−/−-STZ. B: Quantification of protein levels of the MAPK p38 and its phosphorylated form as well as TAB-1 showing a normalization of the p38 activation and the TAB-1 protein content in B1R−/−-STZ compared with B1R+/+-STZ. *P < 0.05 vs. B1R−/−-STZ. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Protein levels of endothelial nitric oxide synthase levels (eNOS) were downregulated in both diabetic groups. Nevertheless, the mRNA content was only downregulated significantly in the the B1R+/+-STZ but not in the B1R−/−-STZ mice (Fig. 4). Furthermore, the phosphorylation state of the MAPK p38, known to contribute to tissue inflammation, was increased in STZ mice compared with controls, again an effect that was reduced in B1R−/−-STZ mice when compared with controls. Moreover, TAB-1 protein was significantly inreased in diabetic wild-type compared with B1R−/−-STZ mice (Fig. 6).

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