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Targeted inhibition of calpain reduces myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes.

Li Y, Ma J, Zhu H, Singh M, Hill D, Greer PA, Arnold JM, Abel ED, Peng T - Diabetes (2011)

Bottom Line: Calpain activity, cardiomyocyte cross-sectional areas, and myocardial collagen deposition were significantly increased in both STZ-induced and OVE26 diabetic hearts, and these were accompanied by elevated expression of hypertrophic and fibrotic collagen genes.These effects were associated with a normalization of the nuclear factor of activated T-cell nuclear factor-κB and matrix metalloproteinase (MMP) activities in diabetic hearts.Thus targeted inhibition of calpain represents a potential novel therapeutic strategy for reversing diabetic cardiomyopathy.

View Article: PubMed Central - PubMed

Affiliation: Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.

ABSTRACT

Objective: Recently we have shown that calpain-1 activation contributes to cardiomyocyte apoptosis induced by hyperglycemia. This study was undertaken to investigate whether targeted disruption of calpain would reduce myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes.

Research design and methods: Diabetes in mice was induced by injection of streptozotocin (STZ), and OVE26 mice were also used as a type 1 diabetic model. The function of calpain was genetically manipulated by cardiomyocyte-specific knockout Capn4 in mice and the use of calpastatin transgenic mice. Myocardial hypertrophy and fibrosis were investigated 2 and 5 months after STZ injection or in OVE26 diabetic mice at the age of 5 months. Cultured isolated adult mouse cardiac fibroblast cells were also investigated under high glucose conditions.

Results: Calpain activity, cardiomyocyte cross-sectional areas, and myocardial collagen deposition were significantly increased in both STZ-induced and OVE26 diabetic hearts, and these were accompanied by elevated expression of hypertrophic and fibrotic collagen genes. Deficiency of Capn4 or overexpression of calpastatin reduced myocardial hypertrophy and fibrosis in both diabetic models, leading to the improvement of myocardial function. These effects were associated with a normalization of the nuclear factor of activated T-cell nuclear factor-κB and matrix metalloproteinase (MMP) activities in diabetic hearts. In cultured cardiac fibroblasts, high glucose-induced proliferation and MMP activities were prevented by calpain inhibition.

Conclusions: Myocardial hypertrophy and fibrosis in diabetic mice are attenuated by reduction of calpain function. Thus targeted inhibition of calpain represents a potential novel therapeutic strategy for reversing diabetic cardiomyopathy.

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Related in: MedlinePlus

Cardiac function. Tg-CAST, Capn4−/− (knockout [KO]), and wild-type (WT) mice were injected with STZ. Two (Tg-CAST) or five months (Capn4−/−) after STZ injection, in vivo hemodynamic measurement was performed. Changes in −dP/dtmin (A and C) and LV stiffness (B and D) are shown. Data are mean ± SD; n = 6–10 per group. *P < 0.05 vs. WT sham; #P < 0.05 vs. WT STZ. Two months after STZ injection, mouse hearts were isolated and perfused in a Langendorff system. Contractile function of the heart was determined. Changes in the rate of contraction (+dF/dtmax; E and G) and relaxation (−dF/dtmin; F and H) are presented. Data are mean ± SD; n = 8 to 9 per group. *P < 0.05 vs. WT sham; #P < 0.05 vs. WT STZ.
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Figure 8: Cardiac function. Tg-CAST, Capn4−/− (knockout [KO]), and wild-type (WT) mice were injected with STZ. Two (Tg-CAST) or five months (Capn4−/−) after STZ injection, in vivo hemodynamic measurement was performed. Changes in −dP/dtmin (A and C) and LV stiffness (B and D) are shown. Data are mean ± SD; n = 6–10 per group. *P < 0.05 vs. WT sham; #P < 0.05 vs. WT STZ. Two months after STZ injection, mouse hearts were isolated and perfused in a Langendorff system. Contractile function of the heart was determined. Changes in the rate of contraction (+dF/dtmax; E and G) and relaxation (−dF/dtmin; F and H) are presented. Data are mean ± SD; n = 8 to 9 per group. *P < 0.05 vs. WT sham; #P < 0.05 vs. WT STZ.

Mentions: Having demonstrated the ability of calpastatin and cardiac Capn4 deletion to reverse cardiomyocyte hypertrophy and fibrosis in the diabetic myocardium, we performed in vivo LV pressure–volume measurements and a functional analysis of heart contraction and relaxation using the Langendorff system as an extension of those results. The hemodynamic parameters were shown in Supplementary Tables 2 and 3. As expected, pressure–volume analysis showed significant decreases in maximal positive and minimal negative first derivatives of LV pressure (+dP/dtmax and −dP/dtmin) and increase in LV stiffness in diabetic hearts. However, these changes of −dP/dtmin and stiffness were relatively attenuated in diabetic Capn4−/− and Tg-CAST compared with their wild-type littermates (Fig. 8A–D). Consistently, the decreases of heart contraction and relaxation were also attenuated in isolated calpastatin transgenic and Capn4 knockout hearts after STZ injection (Fig. 8E–H). Taken together, targeted disruption of calpain preserves myocardial function in diabetic cardiomyopathy of STZ-induced type 1 diabetes.


Targeted inhibition of calpain reduces myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes.

Li Y, Ma J, Zhu H, Singh M, Hill D, Greer PA, Arnold JM, Abel ED, Peng T - Diabetes (2011)

Cardiac function. Tg-CAST, Capn4−/− (knockout [KO]), and wild-type (WT) mice were injected with STZ. Two (Tg-CAST) or five months (Capn4−/−) after STZ injection, in vivo hemodynamic measurement was performed. Changes in −dP/dtmin (A and C) and LV stiffness (B and D) are shown. Data are mean ± SD; n = 6–10 per group. *P < 0.05 vs. WT sham; #P < 0.05 vs. WT STZ. Two months after STZ injection, mouse hearts were isolated and perfused in a Langendorff system. Contractile function of the heart was determined. Changes in the rate of contraction (+dF/dtmax; E and G) and relaxation (−dF/dtmin; F and H) are presented. Data are mean ± SD; n = 8 to 9 per group. *P < 0.05 vs. WT sham; #P < 0.05 vs. WT STZ.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3198063&req=5

Figure 8: Cardiac function. Tg-CAST, Capn4−/− (knockout [KO]), and wild-type (WT) mice were injected with STZ. Two (Tg-CAST) or five months (Capn4−/−) after STZ injection, in vivo hemodynamic measurement was performed. Changes in −dP/dtmin (A and C) and LV stiffness (B and D) are shown. Data are mean ± SD; n = 6–10 per group. *P < 0.05 vs. WT sham; #P < 0.05 vs. WT STZ. Two months after STZ injection, mouse hearts were isolated and perfused in a Langendorff system. Contractile function of the heart was determined. Changes in the rate of contraction (+dF/dtmax; E and G) and relaxation (−dF/dtmin; F and H) are presented. Data are mean ± SD; n = 8 to 9 per group. *P < 0.05 vs. WT sham; #P < 0.05 vs. WT STZ.
Mentions: Having demonstrated the ability of calpastatin and cardiac Capn4 deletion to reverse cardiomyocyte hypertrophy and fibrosis in the diabetic myocardium, we performed in vivo LV pressure–volume measurements and a functional analysis of heart contraction and relaxation using the Langendorff system as an extension of those results. The hemodynamic parameters were shown in Supplementary Tables 2 and 3. As expected, pressure–volume analysis showed significant decreases in maximal positive and minimal negative first derivatives of LV pressure (+dP/dtmax and −dP/dtmin) and increase in LV stiffness in diabetic hearts. However, these changes of −dP/dtmin and stiffness were relatively attenuated in diabetic Capn4−/− and Tg-CAST compared with their wild-type littermates (Fig. 8A–D). Consistently, the decreases of heart contraction and relaxation were also attenuated in isolated calpastatin transgenic and Capn4 knockout hearts after STZ injection (Fig. 8E–H). Taken together, targeted disruption of calpain preserves myocardial function in diabetic cardiomyopathy of STZ-induced type 1 diabetes.

Bottom Line: Calpain activity, cardiomyocyte cross-sectional areas, and myocardial collagen deposition were significantly increased in both STZ-induced and OVE26 diabetic hearts, and these were accompanied by elevated expression of hypertrophic and fibrotic collagen genes.These effects were associated with a normalization of the nuclear factor of activated T-cell nuclear factor-κB and matrix metalloproteinase (MMP) activities in diabetic hearts.Thus targeted inhibition of calpain represents a potential novel therapeutic strategy for reversing diabetic cardiomyopathy.

View Article: PubMed Central - PubMed

Affiliation: Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.

ABSTRACT

Objective: Recently we have shown that calpain-1 activation contributes to cardiomyocyte apoptosis induced by hyperglycemia. This study was undertaken to investigate whether targeted disruption of calpain would reduce myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes.

Research design and methods: Diabetes in mice was induced by injection of streptozotocin (STZ), and OVE26 mice were also used as a type 1 diabetic model. The function of calpain was genetically manipulated by cardiomyocyte-specific knockout Capn4 in mice and the use of calpastatin transgenic mice. Myocardial hypertrophy and fibrosis were investigated 2 and 5 months after STZ injection or in OVE26 diabetic mice at the age of 5 months. Cultured isolated adult mouse cardiac fibroblast cells were also investigated under high glucose conditions.

Results: Calpain activity, cardiomyocyte cross-sectional areas, and myocardial collagen deposition were significantly increased in both STZ-induced and OVE26 diabetic hearts, and these were accompanied by elevated expression of hypertrophic and fibrotic collagen genes. Deficiency of Capn4 or overexpression of calpastatin reduced myocardial hypertrophy and fibrosis in both diabetic models, leading to the improvement of myocardial function. These effects were associated with a normalization of the nuclear factor of activated T-cell nuclear factor-κB and matrix metalloproteinase (MMP) activities in diabetic hearts. In cultured cardiac fibroblasts, high glucose-induced proliferation and MMP activities were prevented by calpain inhibition.

Conclusions: Myocardial hypertrophy and fibrosis in diabetic mice are attenuated by reduction of calpain function. Thus targeted inhibition of calpain represents a potential novel therapeutic strategy for reversing diabetic cardiomyopathy.

Show MeSH
Related in: MedlinePlus