The role of the peroxisome proliferator-activated receptor alpha pathway in pathological remodeling of the diabetic heart.

PURPOSE OF REVIEW

Cardiovascular disease is exceptionally prevalent in patients with diabetes mellitus, which is an emerging pandemic. Unfortunately, the pathogenesis of diabetic myocardial disease is still poorly understood.

RECENT FINDINGS

Evidence has emerged that perturbed cardiac energy metabolism (excessive dependence on fatty acid utilization and diminished carbohydrate metabolism) plays a role in the development of myocardial dysfunction in diabetes. In support of this, transgenic mice with cardiac-specific activation of the peroxisome proliferator-activated receptor alpha, a nuclear receptor transcription factor that enhances the expression of myriad genes controlling cellular fatty acid utilization, exhibit several classic signatures of the diabetic heart. In particular, the hearts of these mice display: increased import, oxidation, and storage of fatty acids; strong counter-regulatory inhibition of glucose import and oxidation; and cardiomyopathic remodeling and dysfunction. A high-fat diet exacerbates the cardiomyopathic phenotype in peroxisome proliferator-activated receptor alpha transgenic mice in a completely reversible manner. The dysfunctional phenotype and its resolution correlates with levels of several potential toxic mediators, including triglycerides, ceramide, and reactive oxygen species. These findings contrast with several studies demonstrating beneficial effects of peroxisome proliferator-activated receptor alpha ligands in the treatment of type 2 diabetes.

SUMMARY

Such studies provide a rationale for greater emphasis on serum lipid-lowering strategies and the control of dietary fat content in the treatment of diabetic cardiomyopathy. Moreover, the use of peroxisome proliferator-activated receptor alpha activators or related compounds as therapeutic agents will require rigorous evaluation of the effects on cardiac function in the diabetic patient.