Inhibition of the Renin-Angiotensin System Prevents Free Fatty Acid–Induced Acute Endothelial Dysfunction in Humans

Abstract

Objective-An elevated free fatty acid (FFA) level impairs endothelium-dependent vasodilation in humans, which may be pathophysiologically relevant to the development of endothelial dysfunction in patients with insulin resistance. We investigated the effect of inhibition of the renin-angiotensin system (RAS) on FFA-induced endothelial dysfunction. Methods and Results-Changes in forearm blood flow during intra-arterial infusion of acetylcholine were measured by plethysmography before and after systemic infusion of lipid/heparin in 10 healthy subjects given a single dose of placebo, losartan (50 mg), or perindopril (8 mg). Endothelial function after lipid/heparin infusion was also investigated with the coinfusion of vitamin C or N G -monomethyl-L-arginine (L-NMMA). Elevated FFA significantly reduced the response to acetylcholine by 37.7% (Pϭ0.0096) without L-NMMA, but not the response with L-NMMA, whereas FFA did not affect the response to nitroprusside. The single dose of either losartan or perindopril completely prevented FFA-induced endothelial dysfunction. Vitamin C also prevented FFA-induced endothelial dysfunction. Conclusions-Elevated FFA levels by lipid/heparin infusion, which may partly mimic the abnormal lipid profile in patients with insulin resistance, caused endothelial dysfunction via RAS activation and the presumably resultant oxidative stress in humans. Our results suggest the therapeutic rationale for RAS inhibition in patients with high FFA levels. Key Words: fatty acids Ⅲ endothelium Ⅲ angiotensin II Ⅲ insulin resistance Ⅲ nitric oxide A n increased plasma level of free fatty acid (FFA) may play pivotal roles in the development and progression of endothelial dysfunction and insulin resistance in patients with type 2 diabetes as well as in the prediabetic state, including the metabolic syndrome and visceral adiposity. 1,2 In addition to a negative correlation between plasma FFA levels and endothelial function, 3 a direct vascular effect of FFA on endothelial function in humans has already been demonstrated. FFAs elevated by lipid/heparin infusion significantly attenuated the vasodilatory response to acetylcholine (ACh) in healthy subjects. 2,4 Although it has been suggested that reactive oxygen species 4 -6 and activation of a stress-sensitive pathway like the transcriptional factor nuclear factor-B 7,8 may be involved in FFA-induced endothelial dysfunction, no specific therapeutic intervention has yet been established.Several randomized, clinical trials have suggested that inhibition of the renin-angiotensin system (RAS) is particularly effective in patients with diabetic hypertension compared with nondiabetic hypertension. 9,10 Improvement in endothelial function by angiotensin-converting enzyme (ACE) inhibitors 11 and angiotensin II type 1 receptor (AT 1 ) antagonists (ARB) 12 in type 2 diabetic patients may partly explain the results of previous randomized, clinical trials. Moreover, there is much evidence in support of enhanced activity of the RAS in obese, hypertensive patients. 13 In the pr...

Free Fatty Acid Causes Leukocyte Activation and Resultant Endothelial Dysfunction Through Enhanced Angiotensin II Production in Mononuclear and Polymorphonuclear Cells

“…9 Our results strongly suggest that activated RAS predominantly contributes to FFA-induced endothelial dysfunction; however, the specific RAS systems that are involved must be identified. The experiments in the present study have partly identified these RAS systems.…”

“…Therefore, one simple and plausible explanation for FFAinduced, RAS-mediated endothelial dysfunction is the enhancement of NADPH oxidase activity and reactive oxygen species production in endothelial cells by Ang II from leukocytes. In fact, we demonstrated previously that vitamin C prevented FFA-induced endothelial dysfunction in humans 9 and that palmitate enhanced reactive oxygen species production and NADPH oxidase expression. 13 However, the enhanced release of Ang II from leukocytes, if any, was not detectable as changes in the plasma concentration of Ang II, the systemic blood pressure, or the forearm vascular tone in the present study, which raises doubts that the increased Ang II production in leukocytes could be functionally relevant to vascular function.…”

“…6 These observations, together with results from epidemiological studies, 7,8 suggest that FFA is involved in atherosclerosis in subjects with insulin resistance. Recently, we have found that FFA-induced endothelial dysfunction is prevented by the inhibition of the renin-angiotensin (Ang) system (RAS) in humans, 9 suggesting that RAS activation by FFA may predominantly contribute to FFA-induced endothelial dysfunction. This hypothesis appears plausible because of the close relationship between obesity and RAS activity in humans.…”

Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome

“…They enhance skeletal muscle blood flow, improving insulin delivery and enhancing glucose uptake and metabolism in insulin-sensitive tissues [25,142,143].They also improve insulin-mediated glucose uptake by reducing the degradation of bradykinin and increasing the production of NO through their blockade of kininase II and ACE [133,144]. They enhance vascular sensitivity to insulin and improve endothelial function [145,146]. ACE inhibitors may prevent or reduce Ang II-mediated interference with insulin-signaling pathways, evidenced by increased glucose transporter-4 protein content in skeletal muscle [147].…”

Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

“…[35][36][37][38][39] In this study, we found excessive abnormal lipid accumulation in the renal tissue of SHR-HF animals compared with that in WKY-HF groups, which was related to increases in the mesangial matrix, TGF-b1 expression, apoptotic glomerular cells and the infiltration of inflammatory cells into kidneys. These findings are consistent with those of previous studies showing that lipid accumulation in kidneys promotes glomerulosclerosis through the low-density lipoprotein-receptor in mesangial cells, through macrophage chemotaxis, increased production of fibrotic cytokines and direct podocyte injury through oxidative stress.…”