Saturated fatty acids induce inflammation in blood vessels

Cyclooxygenase-2 (COX-2) catalyzes the biosynthesis of prostanoids that trigger several normal effects during physiological conditions in the human vasculature. However, in pathophysiological conditions the inflammation induced by COX-2 activity may contribute to the development of unstable atherosclerotic plaques or increase the risk of ischemic stroke and heart attack. COX-2 expression is classically induced by cytokines and endotoxins (e.g. lipopolysaccharides), but more recent studies have demonstrated a “sterile” pathway induced by dietary free fatty acids (FFAs) resulting in proinflammatory mediator expression in the human vasculature. Although some researchers have demonstrated the effect of FFAs on the proinflammatory mediator expression of nitric oxide synthase, tumor necrosis factor-α, and interleukin-6 in vascular smooth muscle cells, there is little to no information about the effect of FFAs on the expression, activity, and regulation of COX-2 in the human vasculature. One of the most widespread FFAs in animal and plant food sources is palmitic acid. This necessitates the investigation of its effect on vascular health. Current research suggests palmitate, the anion of palmitic acid at physiological pH, can induce the expression of certain inflammatory markers in the vascular smooth muscle, adipose microvascular endothelial cells and myoblast cell lines of a mouse.

Recently, University of Arizona scientists: Puneet Raman, Lakshmi Madhavpeddi, and Professor Rayna J. Gonzales from the Department of Basic Medical Sciences demonstrated that palmitate elicits a dose-dependent increase in COX-2 protein expression and modulates the regulation of COX-2 activity through the modification of post-translational glycosylation. The work is published in the American Journal of Physiology-Cell Physiology.

The authors observed that the treatment of human primary vascular smooth muscle cells with palmitate resulted in a dose-dependent increase in COX-2 protein levels. They also observed an increase in the more glycosylated form of COX-2, coupled with an increase in the production of downstream inflammatory marker prostaglandin E2 in human primary vascular smooth muscle cells. These effects were attenuated by the treatment of human primary vascular smooth muscle cells with multiple glycosylation inhibitors (tunicamycin and glucosamine hydrochloride). Quantitative increases in cell density and morphological changes were also noted with palmitate treatment, changes that were attenuated by treatment with a functional selective COX-2 inhibitor (NS-398).

“Our research is one of the initial steps in clarifying the link between high fat diet and vascular disease,” Raman said in a statement to Medicine Innovates. “We found a novel mechanism for the inflammation caused by the most common dietary saturated fat. Looking forward, we would like to investigate how other pharmacologic agents can impact the glycosylation and activity of COX-2, a key inflammatory mediator, with the goal of reducing or preventing inflammatory changes in the blood vessel wall. We also see the importance of understanding how unsaturated fatty acids, the ‘healthy fats’, may impact this inflammatory process.”

The University of Arizona study provide compelling evidence that palmitate increases the total protein levels of COX-2 and elicits the regulation of COX-2 activity through posttranslational modification processes that involve glycosylation. These findings will advance further studies on the specific mechanism(s) of palmitate-induced vascular inflammation in the human vasculature for the identification of new potential therapeutic targets for cardiovascular diseases.