Endothelial dysfunction: A strategic target in the treatment of hypertension?

Endothelial dysfunction is a common feature of hypertension, and it results from the imbalanced release of endothelium-derived relaxing factors (EDRFs; in particular, nitric oxide) and endothelium-derived contracting factors (EDCFs; angiotensin II, endothelins, uridine adenosine tetraphosphate, and cyclooxygenase-derived EDCFs). Thus, drugs that increase EDRFs (using direct nitric oxide releasing compounds, tetrahydrobiopterin, or l-arginine supplementation) or decrease EDCF release or actions (using cyclooxygenase inhibitor or thromboxane A2/prostanoid receptor antagonists) would prevent the dysfunction. Many conventional antihypertensive drugs, including angiotensin-converting enzyme inhibitors, calcium channel blockers, and third-generation β-blockers, possess the ability to reverse endothelial dysfunction. Their use is attractive, as they can address arterial blood pressure and vascular tone simultaneously. The severity of endothelial dysfunction correlates with the development of coronary artery disease and predicts future cardiovascular events. Thus, endothelial dysfunction needs to be considered as a strategic target in the treatment of hypertension. © 2010 Springer-Verlag.postprin

Deletion of repressor activator protein 1 modulates vascular function in mouse aorta

First joint meeting between the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) and the British Pharmacological Society (BPS) , in association with the Hong Kong Pharmacology Society (HKPS) and the Asia Pacific Federation of Pharmacologists (APFP)Conference Theme: Tomorrow's medicines: pharmacology, patients and populationsOral presentations 9: Cardiovascular and Respiratory 4published_or_final_versio

Repressor activator protein 1 induces pro-inflammatory cytokines production in macrophages through NFKB signaling

Abstracts for Oral Presentation: no. OP-5This journal issue including abstracts of 18th Annual Scientific Meeting Institute of Cardiovascular Science and MedicineOBJECTIVES: Repressor activator protein 1 (Rap1), an established telomere-associated protein migrates to the cytoplasm and activates nuclear factor kappa B (NFκB) in human carcinoma cell lines. The present study tested the hypothesis that Rap1 induces production of pro-inflammatory cytokines via NFκB signaling in macrophages, a cell type involved in the development and ...postprin

Impaired cold tolerance in EP4 knockout mice is not due to compromised recruitment of UCP1

This journal issue including abstracts of 18th Annual Scientific Meeting Institute of Cardiovascular Science and MedicineAbstracts for Posters: no. P02OBJECTIVE: Uncoupling protein 1 (UCP1) is the key component of beta-adrenergically controlled non-shivering thermogenesis in brown adipose tissue (BAT). Certain white adipose tissue (WAT), upon exposition to cold, can undergo a process knowing as browning where it takes on characteristics of BAT, notably induction of UCP1 and the presence of multilocular lipid droplets and multiple mitochondria. Our preliminary data indicated that mice deficient in EP4 (one subtype of PGE2 receptor) are cold-intolerant, suggesting that EP4 influence thermogenesis capacity. The aim of this project was to investigate whether or not the impaired thermogenesis in ...postprin

Knockdown of repressor activator protein 1 facilitated foam cell formation by augmenting cholesterol uptake

This journal issue including abstracts of 18th Annual Scientific Meeting Institute of Cardiovascular Science and MedicineAbstracts for Oral Presentation: no. OP-1OBJECTIVES: Repressor activator protein 1 (Rap1) is a telomere-associated protein with telomeric-regulating functions, but it also displays non-telomeric functions and regulates metabolism. The expression of Rap1 is enhanced in atherosclerotic plaques. Presence of foam cells is an indicator of plaque buildup. This study aims to investigate if Rap1 knockdown has an ...postprin

Thyroid hormone affects both endothelial and vascular smooth muscle cells in rat arteries

Hypothyroidism impairs endothelium-dependent dilatations, while hyperthyroidism augments the production of endothelial nitric oxide. Thus, experiments were designed to determine if thyroid hormone causes endothelium-dependent responses, or alleviates diabetic endothelial dysfunction. Isometric tension was measured in rings with or without endothelium of arteries from normal and diabetic Sprague-Dawley rats. Release of 6-keto prostaglandin F1α and thromboxane B2 were measured by enzyme linked immunosorbent assay and protein levels [endothelial nitric oxide synthase (eNOS), cyclooxygenases (COX)] by immunoblotting. Triiodothyronine (T3) caused concentration-dependent (3×10−6–3×10−5 M) relaxations in mesenteric (pEC50, 4.96±0.19) and femoral (pEC50, 4.57±0.35) arteries without endothelium. In femoral arteries of rats with diabetes, 5-methylamino-2-[[(2S,3R,5R,8S,9S)-3,5,9-trimethyl-2-(1-oxo-(1H-pyrrol-2- -yl)propan-2-yl)-1,7-dioxaspiro-(5,5)undecan-8-yl]methyl]benzooxazole-4-carboxylic acid (A23187, 3×10−7 to 10−6 M) caused partly endothelium-dependent contractions. After chronic T3-treatment with (10 μg/kg/day; four weeks), the contractions to A23187 of preparations with and without endothelium were comparable, the thromboxane B2-release was reduced (by 38.1±9.2%). The pEC50 of 9, 11-dideoxy-11α, 9α-epoxymethanoprostaglandin F2α (U46619, TP-receptor agonist) was increased in T3-treated diabetic rats compared with controls (8.53±0.06 vs 7.94±0.09). The protein expression of eNOS increased (by 228%) but that of COX-1 decreased (by 35%) after chronic T3 treatment. In human umbilical vein endothelial cells incubated for one week with T3 (10−10–10−7 M) in the presence but not in the absence of interleukin-1β (1 ng/ml), the expression of eNOS was increased compared to control. In conclusion, thyroid hormone acutely relaxes mesenteric and femoral vascular smooth muscle, but given chronically reduces the release of endothelium-derived vasoconstrictor prostanoids while enhancing the responsiveness of TP receptors of vascular smooth muscle.postprin

Prostaglandin E Receptor Subtype 4 Signaling in the Heart: Role in Ischemia/Reperfusion Injury and Cardiac Hypertrophy

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Immunosuppressive mechanisms of human bone marrow derived mesenchymal stromal cells in BALB/c host graft versus host disease murine models

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COX-2 inhibition protects against hypoxia/reoxygenation-induced cardiomyocyte apoptosis via Akt-dependent enhancement of iNOS expression

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Endothelium-derived Vasoactive Factors and Hypertension: Possible Roles in Pathogenesis and as Treatment Targets

Endothelial cells regulate vascular tone by releasing various contracting and relaxing factors including nitric oxide (NO), arachidonic acid metabolites (derived from cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases), reactive oxygen species, and vasoactive peptides. Additionally, another pathway associated with the hyperpolarization of the underlying smooth muscle cells plays a predominant role in resistance arteries. Endothelial dysfunction is a multifaceted disorder, which has been associated with hypertension of diverse etiologies, involving not only alterations of the L-arginine NO-synthase–soluble guanylyl cyclase pathway but also reduced endothelium-dependent hyperpolarizations and enhanced production of contracting factors, particularly vasoconstrictor prostanoids. This brief review highlights these different endothelial pathways as potential drug targets for novel treatments in hypertension and the associated endothelial dysfunction and end-organ damage