Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia

Area of Science:

• Cardiovascular Biology
• Metabolic Pathways
• Enzymology

Background:

• Aldose reductase (AR) is implicated in diabetic complications and cardiac ischemic injury.
• The role of AR specifically within cardiomyocytes in these pathologies remains unclear.
• Understanding AR's cardiac function is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the impact of cardiomyocyte-specific aldose reductase overexpression on cardiac function.
• To determine if AR contributes to cardiac dysfunction during aging and altered substrate metabolism.
• To evaluate the therapeutic potential of AR inhibition in cardiac ischemia and heart failure.

Main Methods:

• Generation of transgenic mice with cardiac-specific expression of human aldose reductase (hAR) using the α-myosin heavy chain (MHC) promoter.
• Assessment of cardiac function, gene expression, and metabolic profiles in young and aged hAR transgenic mice.
• Evaluation of cardiac injury and functional recovery following ischemia-reperfusion in hAR transgenic and wild-type littermates.
• Crossbreeding hAR transgenic mice with PPAR alpha knockout mice to study combined effects on cardiac metabolism and pathology.

Main Results:

• Cardiac hAR overexpression did not affect cardiac function or glucose/fatty acid oxidation gene expression in young mice.
• Aged hAR transgenic mice exhibited significant cardiac dysfunction.
• hAR transgenic mice showed increased infarct size and impaired functional recovery after ischemia-reperfusion.
• In a model of reduced fatty acid oxidation, hAR expression led to increased cardiac fructose, fibrosis, reactive oxygen species (ROS), and apoptosis.

Conclusions:

• Overexpression of aldose reductase in cardiomyocytes induces cardiac dysfunction during aging and under conditions of reduced fatty acid and increased glucose metabolism.
• These findings highlight a detrimental role for AR in the heart, particularly in pathological settings.
• Pharmacological inhibition of aldose reductase presents a promising therapeutic strategy for ischemia and certain types of heart failure.