Vascular effects of non-esterified fatty acids: implications for the cardiovascular risk factor cluster.

Insulin resistance emerges as a central component of the risk factor cluster and is a likely contributor to vascular disease independently of traditional risk factors such as hypertension and diabetes mellitus. However, the intermediary mechanisms by which atherosclerosis is accelerated among patients with the insulin resistance syndrome remain inadequately defined. Most of the attention has centered on hyperinsulinemia and defects of insulin-mediated glucose disposal. However, we observed that obese hypertensive patients have elevated plasma concentrations of non-esterified fatty acids (NEFAs), including oleic acid, which are highly resistant to suppression by insulin. Resistance to insulin's fatty acid lowering action correlate with blood pressure in obese subjects independently of defects in glucose disposal. This observation raises the possibility that NEFAs have biologically significant effects on the cardiovascular system. In fact, oleic acid impairs nitric oxide synthase activity and endothelium-dependent vasorelaxation in vitro. Moreover, raising NEFAs in normal human volunteers to levels observed in obese hypertensive patients impairs lower extremity endothelium-dependent vasodilation and augments local and systemic vascular alpha1-adrenoceptor reactivity in normal volunteers. Thus, raising NEFAs replicates in healthy subjects important functional vascular changes implicated in the hypertension and atherosclerosis observed in patients with the risk factor cluster. At a molecular level, experiments in cultured vascular smooth muscle cells demonstrate that oleic acid activates a mitogenic signaling cascade which includes protein kinase C, reactive oxygen species and extracellular signal-regulated kinases. Each of these signaling events has been implicated in the structural and functional vascular changes which accompany the risk factor cluster. Collectively, these observations raise the possibility that fatty acids contribute to functional and structural vascular changes among insulin-resistant individuals. A better understanding of the signaling mechanisms by which NEFAs exert their vascular effects may facilitate novel and more effective therapeutic approaches to managing the cardiovascular risk factor cluster.