© 2002 American Heart Association, Inc.
Editorials |
Vascular Dysfunction in Hyperglycemia
Is Protein Kinase C the Culprit?
From the Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wis.
Correspondence to David D. Gutterman, MD, Professor and Associate Director, Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail dgutt@mcw.edu
Key Words: protein kinase C • diabetes • vasodilation • therapeutics • human
Diabetes mellitus (DM) is the seventh leading cause of death in the United States with accelerated cardiovascular disease accounting for most (>75%) of the mortality. Major complications include retinopathy, nephropathy, neuropathy, and vasculopathy. Each has been linked to the severity of hyperglycemia; thus, the mainstay of treatment has been to aggressively control serum glucose levels. This practice is supported by the large NIH-sponsored Diabetes Complications and Control Trial that linked control of glucose to delayed onset of complications.1 Other mechanisms may also contribute because restoration of euglycemia does not always abrogate progression of established disease.2 Thus, alternative therapeutic approaches based on an understanding of the mechanisms of glucose-induced end-organ damage are needed.
In the current issue of Circulation Research, Beckman et al3 describe the reversal of hyperglycemia-induced endothelial dysfunction in subjects treated with a novel, selective blocker of protein kinase C (PKC) ß. The role of PKC in the vascular complications of DM has been established in animals. This study represents an important translational extension into the clinical arena supporting the possibility of drug trials. However, to appreciate the role of PKC in diabetic vascular disease, the complexity of mechanisms by which elevated levels of glucose causes tissue damage must be recognized. Three major mechanisms have been proposed.
First, glucose stimulates flux through the sorbitol pathway creating an intracellular reductive redox shift with accumulation of NADPH. This reduces cellular uptake of myoinositol and decreases sodium-potassium ATPase activity. Blocking the sorbitol pathway with aldose reductase inhibitors improves peripheral nerve conduction
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