Eicosapentaenoic acid improves endothelial function and nitric oxide bioavailability in a manner that is enhanced in combination with a statin

Abstract

The endothelium exerts many vasoprotective effects that are largely mediated by release of nitric oxide (NO). Endothelial dysfunction represents an early but reversible step in atherosclerosis and is characterized by a reduction in the bioavailability of NO. Previous studies have shown that eicosapentaenoic acid (EPA), an omega-3 fatty acid (O3FA), and statins individually improve endothelial cell function, but their effects in combination have not been tested. Through a series of in vitro experiments, this study evaluated the effects of a combined treatment of EPA and the active metabolite of atorvastatin (ATM) on endothelial cell function under conditions of oxidative stress. Specifically, the comparative and time-dependent effects of these agents on endothelial dysfunction were examined by measuring the levels of NO and peroxynitrite (ONOO) released from human umbilical vein endothelial cells (HUVECs). The data suggest that combined treatment with EPA and ATM is beneficial to endothelial function and was unique to EPA and ATM since similar improvements could not be recapitulated by substituting another O3FA docosahexaenoic acid (DHA) or other TG-lowering agents such as fenofibrate, niacin, or gemfibrozil. Comparable beneficial effects were observed when HUVECs were pretreated with EPA and ATM before exposure to oxidative stress. Interestingly, the kinetics of EPA-based protection of endothelial function in response to oxidation were found to be significantly different than those of DHA. Lastly, the beneficial effects on endothelial function generated by combined treatment of EPA and ATM were reproduced when this study was expanded to an ex vivo model utilizing rat glomerular endothelial cells. Taken together, these findings suggest that a combined treatment of EPA and ATM can inhibit endothelial dysfunction that occurs in response to conditions such as hyperglycemia, oxidative stress, and dyslipidemia.

New Insights into Mechanisms of Action for Omega-3 Fatty Acids in Atherothrombotic Cardiovascular Disease

“…As such, treatments leading to the reversal of EC dysfunction may lead to benefits in CAD. While both EPA and statins have been shown separately to improve EC function, their effects in combination have only recently been evaluated in experimental models [ 68 •]. EPA can reverse parameters of endothelial dysfunction caused by exposure to oxLDL or high glucose.…”

“…This endothelial function improvement was specifically evidenced by favorable increases in the EC ratio of nitric oxide (NO) to peroxynitrite (ONOO − ) release. In these cells, EPA generated additional benefit with respect to endothelial function as compared to other TG-lowering agents when combined with ATM [ 68 •].…”

“…EPA-mediated effects on the endothelial NO/ONOO − release ratio were independent of any changes in endothelial nitric oxide synthase (eNOS) expression, suggesting that the mechanism responsible for this benefit is related to eNOS efficiency rather than an increase in the total amount of enzyme [ 68 •]. This suggests an improvement in eNOS coupling.…”

Sea Change for Marine Omega-3s

“…44 Omega-3s may also be helpful to decrease abdominal obesity, preserve muscle mass, ameliorate muscle pain after exercise, reduce cerebral atrophy, boost mood, and dampen systemic inflammation. 33,36,45,46 The benefits of marine long chain fatty acids may turn out to be greater in specific subsets of patients, such as those with systolic dysfunction, 32,47,48 low levels of omega-3 fatty acids in the cell membranes, and African Americans, although this will need to be clarified in future RCTs.…”

Eicosapentaenoic Acid and Docosahexaenoic Acid in Endurance Performance and Cardiovascular Function

“…The results show that DHA and EPA supplementation did not attenuate the reduction of muscle work output in response to muscle con- In addition, prolonged sitting impairs leg endothelial function, and this impairment is thought to be mediated by a sustained reduction in FMD. An increase in nitric oxide (NO) bioavailability appears to be a proposed mechanism by which EPA and DHA supplementation enhances endothelial function [39][40][41][42][43]. Therefore, we recently examined whether EPA (0.6 g/day) and DHA (0.26 g/day) supplementation could be an effective strategy for preventing vascular dysfunction of sitting.…”