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Published on: July 10, 2019
Overexpression of hexokinase protects hypoxic and diabetic cardiomyocytes by increasing ATP generation
Insights
Elevating hexokinase activity protects heart cells from damage caused by low oxygen or diabetes. This improves energy production (ATP) and restores cell function, offering a potential therapeutic strategy for heart conditions.
Area of Science:
- Cardiology
- Metabolic research
- Molecular biology
Background:
- Cardiac glucose metabolism is vital for heart function during hypoxia, but declines in diabetes, potentially causing diabetic cardiomyopathy.
- Hexokinase, the enzyme initiating glucose metabolism, has an uncertain role in hypoxic or diabetic hearts.
- Understanding hexokinase's function is key to addressing energy deficits in cardiac conditions.
Purpose of the Study:
- To assess the protective effects of hexokinase and elevated ATP on cardiomyocyte contractility under hypoxic and diabetic conditions.
- To investigate the role of glucose phosphorylation in the cardiac response to hypoxia and diabetes using transgenic mice.
- To determine if enhanced hexokinase activity can preserve cardiac function in models of hypoxia and Type I diabetes.
Main Methods:
- Utilized cardiomyocytes from transgenic mice (Mh) with cardiac-specific yeast hexokinase expression and control mice.
- Exposed cardiomyocytes to 2 hours of hypoxia to evaluate contractility and ATP content.
- Assessed hexokinase's protective effects in Type I diabetic mouse models (OVE26) and diabetic mice with the hexokinase gene (OVE26Mh).
Main Results:
- Hexokinase overexpression did not affect aerobic conditions but significantly improved ATP content (44%) during hypoxia, restoring cardiomyocyte contractility.
- In diabetic cardiomyocytes (aerobic and hypoxic), the hexokinase gene markedly enhanced ATP levels and significantly improved contractility.
- Elevated hexokinase activity demonstrated a clear benefit in preserving cardiomyocyte function under both hypoxic and diabetic stress.
Conclusions:
- Increased hexokinase activity is beneficial for cardiomyocytes experiencing hypoxia or diabetes.
- The protective mechanism involves enhancing cardiomyocyte ATP levels, thereby preserving contractility.
- Targeting hexokinase activity presents a potential therapeutic avenue for managing cardiac dysfunction in hypoxia and diabetes.
Abstract:
Cardiac glucose metabolism is critical to hypoxic cardiac function and hypoxia is known to stimulate glucose metabolism. This increases generation of ATP when mitochondrial respiration is inhibited. In diabetes, cardiac glucose metabolism declines and this may contribute to diabetic cardiomyopathy. The first step in committing glucose to metabolism is glucose phosphorylation catalyzed by hexokinase. But the potential role of hexokinase in the hypoxic or diabetic heart is uncertain. This study is designed to assess the ability of hexo-kinase and elevated ATP to protect cardiomyocyte contractility from hypoxia and diabetes. We used cardiomyocytes from the transgenic mouse Mh, which has cardiac specific expression of yeast hexokinase, to investigate the importance of glucose phosphorylation in the myocyte response to hypoxia and diabetes. Cardiomyocytes were isolated from FVB control and Mh hearts to assess the effects of 2 h of hypoxia on myocyte contractility and ATP content. The protective effect of hexokinase on diabetes was assessed in myocytes from the OVE26 Type I diabetic mouse and in OVE26Mh diabetic mice that carry the hexokinase gene. Overexpression of hexokinase had no effect during aerobic culture, but during hypoxia, hexokinase improved ATP content by 44% and this restored contractility almost to normal levels. In myocytes from diabetic mice, tested under both aerobic and hypoxic conditions, the hexokinase gene significantly improved ATP content and this significantly improved contractility. These results demonstrate that elevating hexokinase activity can be beneficial to hypoxic or diabetic cardiomyocytes secondary to improving myocyte ATP levels.
