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Ablation of Matrix Metalloproteinase-9 Prevents Cardiomyocytes Contractile Dysfunction in Diabetics
Priyanka Prathipati1, Naira Metreveli2, Shyam Sundar Nandi1
1Department of Cellular and Integrative Physiology, University of Nebraska Medical Center Omaha, NE, USA.
Abstract:
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.
Insights
Matrix metalloproteinase-9 (MMP9) impairs heart cell contractility in diabetes. Ablating MMP9 in diabetic mice prevented these negative effects, suggesting MMP9 is a key regulator of heart cell function.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Diabetic Complications
Background:
- Diabetic hearts exhibit elevated matrix metalloproteinase-9 (MMP9) and reduced cardiomyocyte contractility.
- The precise role of MMP9 in regulating cardiomyocyte contractility within the diabetic heart remains unclear.
Purpose of the Study:
- To investigate the hypothesis that MMP9 regulates cardiomyocyte contractility in diabetic hearts.
- To determine if MMP9 ablation prevents impaired cardiomyocyte contractility in a mouse model of type 1 diabetes.
Main Methods:
- Utilized Akita mice (type 1 diabetes model) and MMP9 knockout mice to generate double knockout (DKO) mice.
- Isolated cardiomyocytes to measure contractility and calcium transients.
- Assessed sarco-endoplasmic reticulum calcium ATPase-2a (SERCA-2a) expression and function via qPCR, Western blotting, and immunoprecipitation.
Main Results:
- Akita mice showed decreased cardiomyocyte shortening/re-lengthening rates, prolonged contractility duration, and altered calcium handling compared to WT.
- These functional deficits were significantly blunted in DKO mice.
- SERCA-2a was downregulated in Akita hearts but upregulated in DKO hearts, correlating with functional improvements.
Conclusions:
- MMP9 plays a critical role in regulating cardiomyocyte contractility in diabetic hearts.
- Ablation of MMP9 preserves cardiomyocyte contractility, potentially by restoring SERCA-2a levels and improving calcium transients.
- Targeting MMP9 may offer a therapeutic strategy for diabetic cardiomyopathy.
