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Regulation of contractile proteins in diabetic heart
1Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Amalthotra@Hotmail.com
Insights
Diabetic cardiomyopathy impairs heart function through biochemical defects in contractile proteins. Research shows reduced calcium sensitivity and myosin heavy chain shifts contribute to this dysfunction in diabetic hearts.
Area of Science:
- Cardiology
- Biochemistry
- Molecular Biology
Background:
- Diabetes mellitus is a prevalent chronic condition strongly linked to cardiovascular disease mortality.
- Impaired cardiac function in diabetes, independent of vascular disease, suggests primary myocardial defects.
- Previous research has documented impaired myocardial performance in chronically diabetic animal models.
Purpose of the Study:
- To investigate the role of cardiac contractile and regulatory proteins in the actomyosin system of diabetic cardiomyopathy.
- To define the specific biochemical defects underlying cardiac contractile dysfunction in diabetes.
Main Methods:
- Reconstitution of individual cardiac contractile and regulatory proteins under controlled conditions.
- Analysis of enzymatic data to assess calcium sensitivity in the cardiac actomyosin system.
- Examination of myosin heavy chain (V1-->V3) shifts and troponin I (TnI) phosphorylation.
Main Results:
- Enzymatic data confirmed diminished calcium sensitivity in the cardiac actomyosin system from diabetic hearts.
- Shifts in cardiac myosin heavy chain (V1-->V3) were observed.
- Evidence suggests TnI phosphorylation may contribute to depressed myocardial contractility in experimental diabetes.
Conclusions:
- Biochemical defects in contractile and regulatory proteins, including reduced calcium sensitivity and myosin heavy chain alterations, contribute to impaired cardiac function in diabetic cardiomyopathy.
- These findings highlight independent processes associated with diabetes that affect cardiac performance.
- Further understanding of individual protein function and their coordinated behavior in diabetes is warranted.
Abstract:
Diabetes is one of the most prevalent chronic conditions that has a high association with death from cardiovascular disease(s). An impaired cardiac function independent of vascular disease suggests the existence of a primary myocardial defect in diabetes mellitus. We and others have documented that myocardial performance is impaired in the hearts of chronically diabetic rats and rabbits. Abnormalities in the contractile proteins and regulatory proteins could be responsible for the mechanical defects in streptozotocin (STZ)-diabetic hearts. The major focus of research on contractile proteins in the diabetic state has been on myosin ATPase and its isoenzymes. However, in the contractile protein system, this could be only one of the mechanisms that might be a controlling factor in myofilament contraction in diabetes. To define the role of cardiac contractile as well as regulatory proteins (troponin-tropomyosin) as a whole in the regulation of actomyosin system in diabetic cardiomyopathy, individual proteins of the cardiac system were reconstituted under controlled conditions. Enzymatic data confirmed a diminished calcium sensitivity in the regulation of the cardiac actomyosin system when regulatory protein(s) complex was recombined from diabetic hearts. This diminished calcium sensitivity along with shifts in cardiac myosin heavy chain (V1-->V3) could contribute to the impaired cardiac function in the hearts of chronic diabetic rats. It has also been reported that sarcomeric proteins such as myosin light chain-2 (MLC-2) and troponin I (TnI) could be involved in regulating muscle contraction and in calcium sensitivity. Since phosphorylation of cardiac TnI is associated with altered maximum enzymatic activity and calcium force relationship in isolated muscle preparations. TnI phosphorylation could contribute to depressed myocardial contractility in experimental diabetes. While we have yet to understand the exact function of each component in cardiac muscle and their behavior in concert where all of them act in tandem, we have focussed on the role of contractile proteins and their regulation in diabetes in this review. We have also included a brief discussions on other relevant intracellular components. In summary, there is substantial evidence to suggest that there are independent processes associated with diabetes which effect cardiac performance in experimental animals and in man. The focus of this review has been the explication of a biochemical defect which underlies cardiac contractile dysfunction in experimental models of diabetes.