Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia.

During ischemia and heart failure, there is an increase in cardiac glycolysis. To understand if this is beneficial or detrimental to the heart, we chronically elevated glycolysis by cardiac-specific overexpression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) in transgenic mice. PFK-2 controls the level of fructose-2,6-bisphosphate (Fru-2,6-P2), an important regulator of phosphofructokinase and glycolysis.

Altering and analyzing glucose metabolism in perfused hearts of transgenic mice.

Glucose metabolism plays an important role in cardiac bioenergetics that changes under various stress conditions including hypertrophy, diabetic cardiomyopathy, and ischemia-reperfusion injury. To understand the role of glycolysis under these conditions, we have altered several steps of the glycolytic pathway specifically in the heart. In this chapter, we describe methods used to produce cardiac-targeted transgenic mice and procedures for measuring various glucose metabolites including glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate, and glycogen.

Overexpression of hexokinase protects hypoxic and diabetic cardiomyocytes by increasing ATP generation.

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.

Cardiac expression of kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase inhibits glycolysis, promotes hypertrophy, impairs myocyte function, and reduces insulin sensitivity.

Glycolysis is important to cardiac metabolism and reduced glycolysis may contribute to diabetic cardiomyopathy. To understand its role independent of diabetes or hypoxic injury, we modulated glycolysis by cardiac-specific overexpression of kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (kd-PFK-2). PFK-2 controls the level of fructose 2,6-bisphosphate (Fru-2,6-P(2)), an important regulator of glycolysis.

Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes.

Many diabetic patients suffer from a cardiomyopathy that cannot be explained by poor coronary perfusion. Reactive oxygen species (ROS) have been proposed to contribute to this cardiomyopathy. Consistent with this we found evidence for induction of the antioxidant genes for catalase in diabetic OVE26 hearts.

Elevated hexokinase increases cardiac glycolysis in transgenic mice.

Objective: Cardiac glucose metabolism is critical to normal and pathological function. The significance of the first committed metabolic step, glucose phosphorylation, has not been established. In this study a new transgenic model was developed in order to investigate the importance of this enzymatic step in cardiac glycolysis.

Overexpression of metallothionein reduces diabetic cardiomyopathy.

Many diabetic patients suffer from cardiomyopathy, even in the absence of vascular disease. This diabetic cardiomyopathy predisposes patients to heart failure and mortality from myocardial infarction. Evidence from animal models suggests that reactive oxygen species play an important role in the development of diabetic cardiomyopathy.