Effects of α‐lipoic acid on endothelial function in aged diabetic and high‐fat fed rats

Abstract

Background and purpose: This study was conducted to investigate the effects of a-lipoic acid (a-LA) on endothelial function in diabetic and high-fat fed animal models and elucidate the potential mechanism underlying the benefits of a-LA. Experimental approach: Plasma metabolites reflecting glucose and lipid metabolism, endothelial function, urinary albumin excretion (UAE), plasma and aortic malondialdehyde (MDA) and urinary 8-hydroxydeoxyguanosine (8-OHdG) were assessed in non-diabetic controls (Wistar rats), untreated Goto-Kakizaki (GK) diabetic and high-fat fed GK rats (fed with atherogenic diet only, treated with a-LA and treated with vehicle, for 3 months). Vascular eNOS, nitrotyrosine, carbonyl groups and superoxide anion were also assessed in the different groups. Key results: a-LA and soybean oil significantly reduced both total and non-HDL serum cholesterol and triglycerides induced by atherogenic diet. MDA, carbonyl groups, vascular superoxide and 8-OHdG levels were higher in GK and high-fat fed GK groups and fully reversed with a-LA treatment. High-fat fed GK diabetic rats showed significantly reduced endothelial function and increased UAE, effects ameliorated with a-LA. This endothelial dysfunction was associated with decreased NO production, decreased expression of eNOS and increased vascular superoxide production and nitrotyrosine expression. Conclusions and implications: a-LA restores endothelial function and significantly improves systemic and local oxidative stress in high-fat fed GK diabetic rats. Improved endothelial function due to a-LA was at least partially attributed to recoupling of eNOS and increased NO bioavailability and represents a pharmacological approach to prevent major complications associated with type 2 diabetes.

Low-molecular-weight fucoidan protects endothelial function and ameliorates basal hypertension in diabetic Goto-Kakizaki rats

“…[1][2][3][4][5] Importantly, the present study demonstrates that treatment Fucoidan improves endothelial dysfunction W Cui et al of GK rats with LMWF profoundly ameliorated these diabetes-associated disorders, based on the observations that (1) LMWF improved the basal blood pressure and shear stress-induced vasodilation, and protected mesentery integrity in diabetic rats; (2) LMWF ameliorated the pathological changes in endangium and the endothelium-dependent vasodilation, and upregulated NO synthesis in diabetic rats; and (3) mechanistically, LMWF induced an endothelium/ eNOS/NO-dependent vasorelaxation, in particular an enhancement of eNOS phosphorylation at Ser1177 in both Physiologically, endothelium has a fundamental role in maintenance of vascular function and homeostasis. [7][8][9] Under pathological circumstances, such as high glucose, hypertension, or oxidative stress, endothelial dysfunction characterized by a reduction in NO bioavailability is recognized as the hallmark of atherosclerotic diseases and prediction of cardiovascular events. 4,5,7 Because of the multiple risk factors coexisting in diabetes, diabetes patients are more susceptible to endothelial dysfunction and lesions, and eventually suffer cardiovascular complications.…”

“…eNOS has been identified as the enzyme responsible for most of the NO production in vasculature, and it may undergo a harmful change in its enzymology termed 'eNOS uncoupling' , ie, converting from formation of NO to generating O 2 -that further consumes NO, making toxic peroxynitrite (ONOO -) in diabetes. [7][8][9][10] Concomitantly, reduced eNOS expression and NO release may also take place, particularly in persistently stimulated and injured endothelium. 2,7,9 Therefore, functional loss and impaired expression of eNOS in diabetes have major pathophysiologic consequences to vascular function and health.…”

“…[7][8][9][10] Concomitantly, reduced eNOS expression and NO release may also take place, particularly in persistently stimulated and injured endothelium. 2,7,9 Therefore, functional loss and impaired expression of eNOS in diabetes have major pathophysiologic consequences to vascular function and health. 2,7,8 In addition to its well-recognized anti-inflammatory, antioxidative, anticoagulative, and antiaggregative effects, fucoidan also inhibits vascular smooth muscle cell migration and proliferation.…”

The Regulation of Energy Metabolism Pathways Through L-Carnitine Homeostasis

“…L-carnitine also stimulates glucose oxidation in intact fatty acidperfused rat heart (Broderick, 2006). The beneficial effects of L-carnitine supplementation in animal models of diabetes also have been demonstrated (Malone et al, 1999;Malone et al, 2006;Sena et al, 2008). L-carnitine supplementation is believed to be beneficial for diabetic patients (Mingrone, 2004).…”

Molecular Basis for Mercury-Induced Alteration in Endothelial Function: NO and its Modulators

“…Hypercholesterolemia reduces endothelium-dependent relaxations due to increased oxidative stress leading to a reduced bioavailability of NO [97][98][99][100]. Long-term MeHg treatment induces dyslipidemia, characterized by increased serum cholesterol levels in mice [101].…”