Key result
Ablation of the MMP9 gene in diabetic mice prevented cardiomyocyte contractile dysfunction and improved calcium transients, possibly by increasing SERCA-2a expression.
Why the study?
Does genetic ablation of MMP9 prevent cardiomyocyte contractile dysfunction in diabetic mice?
Does genetic ablation of MMP9 prevent cardiomyocyte contractile dysfunction in diabetic mice?
p-value: p=<0.05
Ablation of MMP9 prevents cardiomyocyte contractile dysfunction in diabetic mice, likely by increasing SERCA-2a and calcium transients.
Does not inform clinical practice; leaves open translation of MMP9 targeting to human diabetic cardiomyopathy.
Elevated expression and activity of matrix metalloproteinase-9 (MMP9) and decreased contractility of cardiomyocytes are documented in diabetic hearts. However, it is unclear whether MMP is involved in the regulation of contractility of cardiomyocytes in diabetic hearts. In the present study, we tested the hypothesis that MMP9 regulates contractility of cardiomyocytes in diabetic hearts, and ablation of MMP9 prevents impaired contractility of cardiomyocytes in diabetic hearts. To determine the specific role of MMP9 in cardiomyocyte contractility, we used 12-14 week male WT (normoglycemic sibling of Akita), Akita, and Ins(2+∕-)/MMP9(-∕-) (DKO) mice. DKO mice were generated by cross-breeding male Ins2(+∕-) Akita (T1D) with female MMP9 knockout (MMP9(-∕-)) mice. We isolated cardiomyocytes from the heart of the above three groups of mice and measured their contractility and calcium transients. Moreover, we determined mRNA and protein levels of sarco-endoplasmic reticulum calcium ATPase-2a (SERCA-2a), which is involved in calcium handling during contractility of cardiomyocytes in WT, Akita, and DKO hearts using QPCR, Western blotting and immunoprecipitation, respectively. Our results revealed that in Akita hearts where increased expression and activity of MMP9 is reported, the rates of shortening and re-lengthening (±dL/dt) of cardiomyocytes were decreased, time to 90% peak height and baseline during contractility was increased, rate of calcium decay was increased, and calcium transient was decreased as compared to WT cardiomyocytes. However, these changes in Akita were blunted in DKO cardiomyocytes. The molecular analyses of SERCA-2a in the hearts showed that it was downregulated in Akita as compared to WT but was comparatively upregulated in DKO. These results suggest that abrogation of MMP9 gene prevents contractility of cardiomyocytes, possibly by increasing SERCA-2a and calcium transients. We conclude that MMP9 plays a crucial role in the regulation of contractility of cardiomyocytes in diabetic hearts.
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Prathipati et al. (2016) studied Diabetic cardiomyopathy. MMP9 gene ablation vs. Diabetic Akita mice (MMP9 intact) and WT mice was evaluated on Cardiomyocyte contractility and calcium transients (p=<0.05). Ablation of the MMP9 gene in diabetic mice prevented cardiomyocyte contractile dysfunction and improved calcium transients, possibly by increasing SERCA-2a expression.
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