[Show abstract][Hide abstract] ABSTRACT: Recent evidence highlights the therapeutic potential of peroxisome proliferator-activated receptor-δ (PPARδ) agonists to increase insulin sensitivity in diabetes. However, the role of PPARδ in regulating vascular function is incompletely characterized. We investigate whether PPARδ activation improves endothelial function in diabetic and obese mice. PPARδ knockout (KO) and wild-type (WT) mice fed with high-fat diet and db/db mice were used as diabetic mouse models, compared with PPARδ KO and WT mice on normal diet and db/m(+) mice. Endothelium-dependent relaxation (EDR) was measured by wire myograph. Flow-mediated vasodilatation (FMD) was measured by pressure myograph. Nitric oxide (NO) production was examined in primary endothelial cells from mouse aortae. PPARδ agonist GW1516 restored EDRs in mouse aortae under high-glucose conditions or in db/db mouse aortae ex vivo. After oral treatment with GW1516, EDRs in aortae and FMDs in mesenteric resistance arteries were improved in obese mice in a PPARδ-specific manner. The effects of GW1516 on endothelial function were mediated through phosphatidylinositol 3-kinase (PI3K) and Akt with a subsequent increase of endothelial nitric oxide synthase (eNOS) activity and NO production. The current study demonstrates an endothelial-protective effect of PPARδ agonists in diabetic mice through PI3K/Akt/eNOS signaling, suggesting the therapeutic potential of PPARδ agonists for diabetic vasculopathy.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Capsaicinoids are the active compounds in chili pepper. The present study investigated the effect of capsaicinoids on plasma lipids, functionality of aorta including atherosclerotic plaque development, cholesterol absorption biomarker, fecal sterol excretion, and gene expression of major receptors, enzymes, and transporters involved in cholesterol metabolism. METHODS: Hamsters were divided into five groups and fed a high-cholesterol diet containing 0 % (CON), 0.010 % (LD), 0.015 % (MD), 0.020 % (HD), and 0.030 % (VD) capsaicinoids, respectively, for 6 weeks. Plasma lipids were measured using the enzymatic kits, and the gene expression of transporters, enzymes, and receptors involved in cholesterol absorption and metabolism was quantified using the quantitative PCR. Endothelial function was assessed by measuring the acetylcholine-induced endothelium-dependent relaxations in aorta. RESULTS: Capsaicinoids reduced plasma total cholesterol, non-high-density lipoprotein cholesterol, and triacylglycerols with high-density lipoprotein cholesterol being unaffected. All four experimental groups had a decrease in the atherosclerotic plaque compared with CON. Dietary capsaicinoids increased the fecal excretion of total acidic sterols possibly mediated by up-regulation of cholesterol 7α-hydroxylase and down-regulation of liver X receptor alpha. Plasma sterol analysis demonstrated that capsaicinoids decreased the ratio of plasma campesterol/cholesterol, suggesting they decreased cholesterol absorption. Capsaicinoids could improve the endothelium-dependent relaxations and reduce the endothelium-dependent contractions by inhibiting the gene expression of COX-2. However, no dose-dependent effect of capsaicinoids on these parameters was seen. CONCLUSION: Capsaicinoids were beneficial in improving lipoprotein profile and aortic function in hamsters fed a high-cholesterol diet.
European Journal of Nutrition 03/2012; 52(1). DOI:10.1007/s00394-012-0344-2 · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies indicate uncoupling protein-2 (UCP2) as an antioxidant defense against endothelial dysfunction in hypertension. UCP2 also regulates insulin secretion and action. However, the role of UCP2 in endothelial dysfunction associated with diabetes and obesity is unclear.
UCP2 protects against endothelial dysfunction induced by high-fat diet through inhibition of reactive oxygen species (ROS) production, and subsequent increase of nitric oxide bioavailability.
Endothelium-dependent relaxation (EDR) in aortae and mesenteric arteries in response to acetylcholine was measured in wire myograph. Flow-mediated vasodilatation in 2(nd)-order mesenteric arteries was measured in pressure myograph. ROS production is measured by CM-H(2)DCFDA and DHE fluorescence. High-glucose exposure reduced EDR in mouse aortae, which was exaggerated in UCP2 knockout (KO) mice, whereas UCP2 overexpression by adenoviral infection (AdUCP2) restored the impaired EDR. Impairment of EDR and flow-mediated vasodilatation in aortae and mesenteric arteries from high-fat diet-induced obese mice (DIO) was exaggerated in UCP2KO DIO mice compared with wild-type DIO littermates, whereas AdUCP2 i.v. injection restored both EDR and flow-mediated vasodilatation in DIO mice. Improved EDR in mesenteric arteries was inhibited by nitric oxide synthase inhibitor. UCP2 overexpression also inhibited intracellular ROS production in the en face endothelium of aorta and mesenteric artery of DIO mice, whereas UCP2 deficiency enhanced ROS production.
UCP2 preserves endothelial function through increasing nitric oxide bioavailability secondary to the inhibition of ROS production in the endothelium of obese diabetic mice.
Circulation Research 03/2012; 110(9):1211-6. DOI:10.1161/CIRCRESAHA.111.262170 · 11.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: H(2)S, a gaseous signalling molecule, relaxes blood vessels partly through activation of ATP-sensitive K(+) channels. It is however unclear whether H(2)S or its donors could affect other ion transporting proteins. The present study examined the hypothesis that NaHS, a H(2)S donor inhibits voltage-sensitive Ca(2+) channels and thus relaxes vascular smooth muscle cells (VSMC) in the cerebral arteries. NaHS dilated cerebral arteries from Sprague-Dawley rats with the same potency against pre-contraction by 5-HT and 60 mmol/L KCl, which were unaffected by several K(+) channel blockers, N(G)-nitro-l-arginine methyl ester or indomethacin, as assessed in wire myograph under an isometric condition. Likewise, NaHS also dilated cerebral arteries against myogenic constriction in pressurized myograph under an isobaric condition. NaHS concentration-dependently inhibited CaCl(2)-induced contraction in Ca(2+)-free, 60mM K(+)-containing Krebs solution. Patch clamp recordings showed that NaHS reduced the amplitude of l-type Ca(2+) currents in single myocytes isolated enzymatically from the cerebral artery. Calcium fluorescent imaging using fluo-4 showed a reduced [Ca(2+)](i) in 60 mmol/L KCl-stimulated rat cerebral arteries in response to NaHS. H(2)S precursor l-cysteine-induced relaxation in cerebral arteries was inhibited by cystathionine γ-lyase (CSE) inhibitor dl-propargylglycine. CSE was expressed in cerebral arteries. In summary, NaHS dilates rat cerebral arteries by reducing l-type Ca(2+) currents and suppressing [Ca(2+)](i) of arterial myocyte, indicating that NaHS relaxes cerebral arteries primarily through inhibiting Ca(2+) influx via Ca(2+) channels.
Pharmacological Research 11/2011; 65(2):239-46. DOI:10.1016/j.phrs.2011.11.006 · 3.98 Impact Factor