thromboxane-a2 and Metabolic-Syndrome

Background Metabolic syndrome is characterized by insulin resistance, which impairs intracellular signaling pathways and endothelial NO bioactivity, leading to cardiovascular complications. Extracellular signal-regulated kinase (ERK) is a major component of insulin signaling cascades that can be activated by many vasoactive peptides, hormones, and cytokines that are elevated in metabolic syndrome. The aim of this study was to clarify the role of endothelial ERK2 in vivo on NO bioactivity and insulin resistance in a mouse model of metabolic syndrome. Methods and Results Control and endothelial-specific ERK2 knockout mice were fed a high-fat/high-sucrose diet (HFHSD) for 24 weeks. Systolic blood pressure, endothelial function, and glucose metabolism were investigated. Systolic blood pressure was lowered with increased NO products and decreased thromboxane A2/prostanoid (TP) products in HFHSD-fed ERK2 knockout mice, and Nω-nitro-l-arginine methyl ester (L-NAME) increased it to the levels observed in HFHSD-fed controls. Acetylcholine-induced relaxation of aortic rings was increased, and aortic superoxide level was lowered in HFHSD-fed ERK2 knockout mice. S18886, an antagonist of the TP receptor, improved endothelial function and decreased superoxide level only in the rings from HFHSD-fed controls. Glucose intolerance and the impaired insulin sensitivity were blunted in HFHSD-fed ERK2 knockout mice without changes in body weight. In vivo, S18886 improved endothelial dysfunction, systolic blood pressure, fasting serum glucose and insulin levels, and suppressed nonalcoholic fatty liver disease scores only in HFHSD-fed controls. Conclusions Endothelial ERK2 increased superoxide level and decreased NO bioactivity, resulting in the deterioration of endothelial function, insulin resistance, and steatohepatitis, which were improved by a TP receptor antagonist, in a mouse model of metabolic syndrome.

Topics: Animals; Extracellular Signal-Regulated MAP Kinases; Insulin; Insulin Resistance; Metabolic Syndrome; Mice; Mice, Knockout; Prostaglandins; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2

Topics: Animals; Atorvastatin; Biomarkers; Disease Models, Animal; Epoprostenol; Hemodynamics; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Metabolic Syndrome; Microcirculation; Microvessels; Models, Cardiovascular; Muscle, Skeletal; Nitric Oxide; Oxygen Consumption; Peripheral Vascular Diseases; Physical Conditioning, Animal; Physical Exertion; Rats, Zucker; Regional Blood Flow; Running; Thromboxane A2; Time Factors

Topics: Angina Pectoris; Atherosclerosis; Blood Specimen Collection; Cardiovascular Agents; Coronary Angiography; Edetic Acid; Humans; Mean Platelet Volume; Metabolic Syndrome; Thromboxane A2

We have studied the vasoactive role of prostaglandins derived from perivascular adipose tissue (PVAT) and their effects on endothelial function in healthy rats and rats with metabolic syndrome (SHROB).. Mesenteric resistance arteries (MRA) from SHROB and control rats (WKY) were mounted on wire myographs: a) together with a sphere of naturally occurring perivascular adipose tissue (with-PVAT group), or b) dissecting all the adventitial tissue (without-PVAT group).. Endothelial function, tested by acetylcholine reactivity of SHROB arteries with PVAT, was significantly lower than that of WKY. With-PVAT arteries, especially the SHROB, showed lower responses than those without PVAT. NO synthase inhibition diminished the acetylcholine responses in every group except the with-PVAT SHROB group. Blockade of cyclooxygenase-2, PGI2-IP, TXA2-TP, or TXA2 synthase increased to different extents the arterial responses in the SHROB with-PVAT group. PVAT from both rat strains revealed cyclooxygenase-2 activity and immunoassay confirmed the release of PGE2, PGI2 and TXA2.. Our major finding is that PVAT is a source of vasoactive prostaglandins in WKY and SHROB. We also report that the presence of visceral PVAT causes endothelial dysfunction of resistance arteries in the SHROB. The vascular responses to prostaglandins partly underlie the endothelial dysfunction of SHROB arteries.

Topics: Acetylcholine; Animals; Cyclooxygenase 2 Inhibitors; Dinoprostone; Endothelium, Vascular; Epoprostenol; In Vitro Techniques; Intra-Abdominal Fat; Male; Mesenteric Arteries; Metabolic Syndrome; NG-Nitroarginine Methyl Ester; Nitric Oxide; Prostaglandins; Rats; Rats, Inbred WKY; Rats, Mutant Strains; Thromboxane A2; Thromboxane-A Synthase; Vascular Resistance; Vasoconstriction; Vasodilation

Topics: Angiotensin II Type 1 Receptor Blockers; Cyclooxygenase 2 Inhibitors; Dinoprost; Humans; Intercellular Adhesion Molecule-1; Losartan; Metabolic Syndrome; PPAR gamma; Receptor, Angiotensin, Type 1; Thromboxane A2

1.-- In the rat, a fructose-enriched diet induces hyperglycaemia, hypertriglyceridaemia, insulin resistance and hypertension; a model which resembles the human metabolic syndrome. 2.-- Prostanoids, metabolites of arachidonic acid, include vasoactive substances synthesized and released from the vascular wall that have been implicated in the increase of peripheral resistance, one of the mechanisms involved in the fructose-induced hypertension. 3.-- The aim of the present study was to: (i) analyse the effects of the in vitro incubation with fructose on the production and release of prostanoids in rat thoracic aorta and in rat mesenteric bed and (ii) compare the effects of incubation with those of the in vivo acute and chronic treatment of rats with fructose and with the combination of both in vivo and in vitro procedures. 4.-- Blood pressure, glycaemia and triglyceridaemia were significantly elevated in both 4- and 22-week fructose-treated groups. Meanwhile, body and heart weight as well as insulinaemia were similar between experimental animals and controls. 5.-- In aortae, 4 weeks of Fructose treatment did not modify the prostanoid pattern release, but in vitro incubation decreased prostacyclin (PGI(2)) production. However, after 22 weeks, fructose treatment and incubation exerted the same effect. 6.-- In mesenteric bed, after 4 weeks, the incubation and the combination of both procedures reduced the release of the vasodilators PGI(2) and PGE(2), while fructose treatment only diminished the PGE(2) release. On the contrary, the production of the vasoconstrictor thromboxane A(2) (TXA(2)) was enhanced by incubation and both the procedures. After 22 weeks, fructose treatment increased PGI(2) release, while it was reduced by incubation. The combination of both did not modify this peripheral resistance when compared with controls. Finally, incubation of tissues from treated rats increased the release of the vasoconstrictors, PGF(2alpha) and TXA(2). 7.-- In conclusion, the mesenteric bed, a resistance vascular bed, seems to be more sensitive than the aorta, a conductance vessel, to the effects of fructose on prostanoid production. This difference could be related to a more relevant role of resistance vessels in the regulation of peripheral resistance and consequently of blood pressure. The observed effects should contribute to a shift in the balance of the release of prostanoid in favour of vasoconstrictor metabolites. This phenomenon could be related to an increa

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Aorta, Thoracic; Blood Pressure; Dinoprostone; Disease Models, Animal; Fructose; Hypertension; In Vitro Techniques; Male; Mesenteric Arteries; Mesenteric Veins; Metabolic Syndrome; Prostaglandins; Rats; Rats, Sprague-Dawley; Thromboxane A2