Enzyme May Speed Artery Thickening in Diabetes

Elevated levels of an enzyme in the endothelium might be a mechanism for accelerated atherosclerosis in diabetes, an animal model study suggested.

Protein kinase C (PKC) beta overexpression in atherosclerosis-prone mice on a Western-style diet was associated with 39% less insulin-induced nitric oxide activation in endothelial cells and 70% more atherosclerosis, George King, MD, of the Joslin Diabetes Center in Boston, and colleagues found.

"These findings may help explain the elevated risk for atherosclerosis in diabetic and insulin-resistant states since PKC activation, especially the beta isoform, has been shown to be induced by hyperglycemia or elevated free fatty acids in many vascular tissues," the group wrote online in Circulation Research.

While the results move the understanding of atherogenesis and diabetic macrovascular complications a step forward, they also point to a treatment strategy, the researchers noted.

Inhibition of PKC beta could be helpful in "preventing atherosclerosis in insulin resistance, type 2 diabetes and other insulin resistant-related diseases" and also "may be a promising treatment of macrovascular complications in diabetic patients," they proposed.

Prior studies had already established that hyperglycemia and high fatty acid levels crank up production of PKC beta, which when activated in endothelial cells in diabetes causes endothelial dysfunction.

So the researchers took mice unable to produce apolipoprotein E to clear cholesterol and other fats from circulation and fed them a high-fat diet for 12 weeks to further provoke atherosclerosis.

Some of these mice were treated with a transgenic factor to make them overexpress the PKC beta-2 isoform in endothelial cells.

Overall insulin sensitivity, glucose tolerance, plasma lipids, and blood pressure didn't differ between the PKC beta over-producers and the other mice.

But within the blood vessel walls, it was a different story.

Insulin action was substantially lower in endothelial cells and the femoral artery in the high PKC beta group, as measured by activation of Akt (42% difference, P<0.01) and endothelial nitric oxide synthase (39% lower, P<0.01), which plays a key role in arterial relaxation, and by leukocyte-endothelial cell binding.

These mice also had elevated basal and angiotensin-stimulated big endothelin-1 (ET-1) levels and impaired arterial dilation responses.

The severity of atherosclerosis in the aorta was higher in the PKC beta-overexpressing mice as well, with 70% greater mean area covered by aortic atherosclerotic lesions, 2.16-fold more atherosclerotic plaque in the abdominal aorta, and 1.99-fold more necrosis in the plaque (all P<0.05).

Altogether, "this study provided definitive evidence that PKC beta activation in the endothelium will accelerate atherosclerosis," the researchers concluded.

The study was supported by NIH grant funds.

Two authors reported receiving fellowships from the American Diabetes Association and the Juvenile Diabetes Research Foundation.

The researchers reported no other conflicts of interest.

Title : Enzyme May Speed Artery Thickening in Diabetes
Published on : Monday, July 15, 2013
Category : Diabetes
Post URL : http://internal-med.blogspot.com/2013/07/enzyme-may-speed-artery-thickening-in.html