Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phytoestrogens derived from soybeans reverse endothelial dysfunction in a number of animal models of systemic vascular disease. Based on these studies, we hypothesized that phytoestrogens would reverse chronic hypoxia-induced endothelial dysfunction in rat pulmonary arteries. To test this hypothesis we examined the effect of genistein, the major phytoestrogen found in soybeans, on carbachol-induced relaxation in phenylephrine-constricted pulmonary artery rings isolated from normoxic rats and rats exposed to 14 days of hypobaric hypoxia. Compared with that in normoxic rats, the response to carbachol was impaired in pulmonary arteries isolated from rats exposed to chronic hypoxia. In normoxic rat pulmonary arteries, genistein (30 microM) did not change the maximum relaxation to carbachol. In contrast, genistein significantly enhanced the relaxation response to carbachol in pulmonary arteries from hypoxic rats, restoring it to the levels seen in normoxic rats. 17beta-estradiol (10 microM) and daidzein (30 microM), a structural analog of genistein lacking inhibitory effects on tyrosine kinases, also restored the relaxation response to carbachol in hypoxic rat pulmonary arteries. The nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine (100 microM) completely blocked the genistein, daidzein, and 17beta-estradiol-induced restoration of the relaxation response to carbachol, whereas the estrogen receptor antagonist ICI 182,780 (10 microM) had no effect on the relaxation responses. We conclude that the phytoestrogens genistein and daidzein act like estrogen in restoring nitric oxide-mediated relaxation in chronically hypoxic rat pulmonary arteries and that this effect does not appear to be mediated by inhibition of tyrosine kinases or by known estrogen receptors.
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PMID:Phytoestrogens restore nitric oxide-mediated relaxation in isolated pulmonary arteries from chronically hypoxic rats. 1135 18

Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide and regulator of blood flow that plays an important role in blood pressure (BP) elevation in some models of experimental hypertension such as DOCA-salt rat, DOCA-salt-treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt-sensitive rats, angiotensin II-infused rats, and one-kidney, one-clip Goldblatt rats, but not in SHR, two-kidney, one-clip hypertensive rats, transgenic (mREN2)27 rats, or Nomega-nitro-L-arginine methyl ester chronically treated rats. In those models of hypertension in which ET-1 plays a vasoconstrictor role, ET-1 was shown to be overexpressed in the vessel walls, or BP has been lowered by administration of ET(A/B)- and ET(A)-selective receptor antagonists. In these experimental models, endothelin receptor antagonists also regressed vascular growth and inflammation, and improved endothelial dysfunction. Hypertensive rats treated with endothelin antagonists were protected from stroke and renal injury. In hypertensive rats without generalized vascular overproduction of ET-1, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of ET in myocardial ischemia in hypertension. Moderate-to-severe hypertensive patients presented enhanced expression of pre-proET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that this stage of hypertension may respond particularly well to endothelin antagonism. In some hypertensive patients, exaggerated vascular responses to ET-1 were found. Hypertensive patients with coronary artery disease have increased arterial expression of ET-1. Increased plasma levels of immunoreactive ET have been described in African Americans. ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor, and in ischemic heart disease and stroke. Endothelin-1 may also be involved in other forms of vascular disease, including pulmonary hypertension, after angioplasty restenosis, after allograft vasculopathy, and vasculitis. Thus, ET-1 may participate in vascular damage in cardiovascular disease and in BP elevation in experimental models and in human hypertension. Endothelin antagonists could become effective disease-modifying agents in different forms of cardiovascular disease.
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PMID:Role of endothelin-1 in hypertension and vascular disease. 1141 70

Vascular smooth muscle cell (VSMC) proliferation is a prominent feature of the atherosclerotic process that occurs after endothelial injury. Although a vascular wall kallikrein-kinin system has been described, its contribution to vascular disease remains undefined. Because the B(1)-kinin receptor subtype (B1KR) is induced in VSMCs only in response to injury, we hypothesize that this receptor may be mediating critical events in the progression of vascular disease. In the present study, we provide evidence that des-Arg(9)-bradykinin (dABK) (10(-8) M), acting through B1KR, stimulates the phosphorylation of mitogen-activated protein kinase (MAPK) (p42(mapk) and p44(mapk)). Activation of MAPK by dABK is mediated via a cholera toxin-sensitive pathway and appears to involve protein kinase C, Src kinase, and MAPK kinase. These findings demonstrate that the activation of B1KR in VSMCs leads to the generation of second messengers that converge to activate MAPK and provide a rationale to investigate the mitogenic actions of dABK in vascular injury.
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PMID:Induction of B(1)-kinin receptors in vascular smooth muscle cells: cellular mechanisms of map kinase activation. 1156 39

Endothelial nitric-oxide synthase (eNOS) is an important component of vascular homeostasis. During vascular disease, endothelial cells are exposed to excess reactive oxygen species that can alter cellular phenotype by inducing various signaling pathways. In the current study, we examined the implications of H(2)O(2)-induced signaling for eNOS phosphorylation status and activity in porcine aortic endothelial cells. We found that H(2)O(2) treatment enhanced eNOS activity and NO bioactivity as determined by the conversion of l-[(3)H]arginine to l-[(3)H]citrulline and cellular cGMP content. Concomitant with eNOS activation, H(2)O(2) also activated Akt, increased eNOS phosphorylation at Ser-1177, and decreased eNOS phosphorylation at Thr-495. H(2)O(2)-induced promotion of eNOS activity and modulation of the eNOS phosphorylation status at Ser-1177 and Thr-495 were significantly attenuated by selective inhibitors of Src kinase, the ErbB receptor family, and phosphoinositide 3-kinase (PI 3-K). We found that Akt activation, eNOS Ser-1177 phosphorylation, and eNOS activation by H(2)O(2) were calcium-dependent, whereas eNOS dephosphorylation at Thr-495 was not, suggesting a branch point in the signaling cascade downstream from PI 3-K. Consistent with this, overexpression of a dominant negative isoform of Akt inhibited H(2)O(2)-induced phosphorylation of eNOS at Ser-1177 but not dephosphorylation of eNOS at Thr-495. Together, these data indicate that H(2)O(2) promotes calcium-dependent eNOS activity through a coordinated change in the phosphorylation status of the enzyme mediated by Src- and ErbB receptor-dependent PI 3-K activation. In turn, PI 3-K mediates eNOS Ser-1177 phosphorylation via a calcium- and Akt-dependent pathway, whereas eNOS Thr-495 dephosphorylation does not involve calcium or Akt. This response may represent an attempt by endothelial cells to maintain NO bioactivity under conditions of enhanced oxidative stress.
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PMID:Hydrogen peroxide activates endothelial nitric-oxide synthase through coordinated phosphorylation and dephosphorylation via a phosphoinositide 3-kinase-dependent signaling pathway. 1174 98

E-selectin mediates the rolling of circulating leukocytes on vascular endothelial cells. A polymorphism, in which serine is substituted for arginine at position 128 (S128R) in the EGF domain, has been associated with both early-onset atherosclerosis and SLE. We investigated whether the substitution alters the ligand-binding properties of E-selectin under shear flow by studying the capacity of Chinese hamster ovary cell transfectants expressing wild type (WT) or S128R E-selectin to support interactions of neutrophils, K562 cells or HL60 cells. We initially chose to study non-fucosylated K562 cells. No interactions were observed on WT E-selectin, whereas S128R supported a transient tethering interaction of K562 cells, which was resistant to digestion with either neuraminidase or O-sialoglycoprotein endopeptidase, and, in turn, could result in firm adhesion in the presence of a beta2-integrin. HL60 cells exhibited increased rolling on S128R E-selectin. Although neuraminidase treatment inhibited all HL60 interactions with WT E-selectin, it unmasked transient tethers on S128R. We further observed that S128R recruited significantly more neutrophils than WT E-selectin, without affecting neutrophil rolling velocity. This polymorphism may therefore amplify leukocyte-endothelial cell interactions and may be a factor linking the S128R polymorphism to vascular disease.
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PMID:The S128R polymorphism of E-selectin mediates neuraminidase-resistant tethering of myeloid cells under shear flow. 1178 16

L-Arginine is a semi-essential amino acid that is metabolized to important regulatory molecules. L-Arginine is transported into vascular smooth muscle cells (SMC) by the cationic amino acid transporter (CAT) family of proteins where it is metabolized to nitric oxide (NO), polyamines, or L-proline. Inflammatory mediators, growth factors, and hemodynamic forces stimulate the transport of L-arginine in vascular SMC by inducing CAT gene expression. However, they exert highly specific and divergent regulatory effects on L-arginine metabolism. Inflammatory cytokines induce the expression of inducible NO synthase (iNOS) and direct the metabolism of L-arginine to the antiproliferative gas, NO. In contrast, growth factors stimulate the expression of arginase I and ornithine decarboxylase (ODC) and channel the metabolism of L-arginine to growth stimulatory polyamines. Alternatively, cyclic mechanical strain blocks both iNOS and ODC activity and stimulates arginase I gene expression, directing the metabolism of L-arginine to the formation of L-proline and collagen. Thus, specific biochemical and biophysical stimuli that are found in the circulation regulate the transport and metabolism of L-arginine in vascular SMC. The ability of these physiologically relevant stimuli to upregulate L-arginine transport and generate specific L-arginine metabolites modulates SMC function and may influence the development of vascular disease.
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PMID:Regulation of L-arginine transport and metabolism in vascular smooth muscle cells. 1189 53

Argatroban, a direct thrombin inhibitor derived from arginine, is an effective anticoagulant indicated for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). Argatroban has been used as an alternative anticoagulant in patients with HIT in various clinical conditions including interventional cardiovascular procedures that require anticoagulation. Satisfactory clinical outcomes with acceptable complications have been reported in these patients. Whether argatroban offers additional clinical advantage over conventional heparin therapy in patients without HIT remains unclear. Argatroban has been evaluated as an alternative anticoagulant to replace heparin in various clinical studies, especially in patients with coronary artery disease or cerebral vascular disease. To date, it remains unclear if argatroban is more effective than heparin, although the agent seems to cause less bleeding complications. This article reviews the pharmacology of argatroban and its clinical application beyond the management of HIT, with particular emphasis on interventional cardiology procedure, acute myocardial infarction, unstable angina pectoris, cerebral thrombosis or ischemic stroke, peripheral obstructive arterial disease, and extracorporeal circulation.
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PMID:Argatroban: a direct thrombin inhibitor for heparin-induced thrombocytopenia and other clinical applications. 1197 90

Flow-mediated vasodilatation (FMD) of the brachial artery is used as a measure to quantify endothelial dysfunction. However, FMD after occlusion only is small in healthy people over middle age, but can be increased after handgrip exercise. The aim of this study was to evaluate whether postocclusion vasodilatation after handgrip exercise is mediated by nitric oxide (NO). High frequency ultrasound was used to measure brachial artery diameter at rest and after reactive hyperaemia with and without handgrip exercise during NaCl or NG-monomethyl-L-arginine (L-NMMA) infusion in healthy 60-year-old men. Postocclusion vasodilation was significantly larger after handgrip exercise compared with occlusion only (P=0.0078). Postocclusion vasodilatation was significantly lower after ischaemic handgrip exercise during intra-arterial infusion of L-NMMA compared with infusion of NaCl (P = 0.039). It may be concluded that the increased postocclusion brachial artery vasodilatation observed after ischaemic handgrip exercise is at least partly NO mediated. This modification of the investigation procedure may improve our ability to quantify FMD in subjects with and without vascular disease.
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PMID:Post-occlusion brachial artery vasodilatation after ischaemic handgrip exercise is nitric oxide mediated. 1200 93

Endothelial production of nitric oxide (nitrogen monoxide, NO) has become a major research area in vascular biology. Some of the most important effects that NO exerts in the vascular wall are potentially vasoprotective, because these effects maintain important physiological functions such as vasodilation, anticoagulation, leucocyte adhesion, smooth muscle proliferation, and the antioxidative capacity. During the last 2 decades it has become apparent that a variety of diseases are associated with an impairment of endothelium-dependent NO activity. One of the major causes is believed to be an increased production of reactive oxygen species, in particular superoxide, which have been shown to interfere with many steps of the NO--cyclic guanosine monophosphate (cGMP) pathway. This phenomenon has been found in diverse conditions such as atherosclerosis, hypertension, diabetes, hypercholesterolemia, heart failure, and cigarette smoking. The aim of this review is to examine the cellular and molecular mechanisms whereby NO exerts potentially vasoprotective effects and to discuss pharmacologic approaches targeting the NO pathway in view of their potential to improve endothelial function and to reduce the progression of atherosclerotic vascular disease. We conclude that there is compelling evidence for vasoprotective actions of NO which are mediated by cGMP-dependent and cGMP-independent mechanisms. These effects may contribute to the beneficial effects of established drugs such as ACE inhibitors or statins. Unfortunately, clinical data on the effect of long-term treatment with nitrates on the progression of coronary artery disease are lacking. Finally, L-arginine or new activators of the NO pathway may become therapeutic options in the future.
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PMID:Vasoprotection by nitric oxide: mechanisms and therapeutic potential. 1212 64

OBJECTIVE-Impaired endothelial function of resistance and conduit arteries can be detected in patients with type 1 diabetes. We studied whether a persistent improvement of endothelial function can be achieved by regular physical training. RESEARCH DESIGN AND METHODS-The study included 26 patients with type 1 diabetes of 20 +/- 10 years' duration and no overt angiopathy; 18 patients (42 +/- 10 years old) participated in a bicycle exercise training program, and 8 patients with type 1 diabetes (33 +/- 11 years old) served as control subjects. Vascular function of conduit arteries was assessed by flow-mediated and endothelium-independent dilation of the brachial artery and of resistance vessels by the response of ocular fundus pulsation amplitudes to intravenous N(G)-monomethyl-L-arginine (L-NMMA) at baseline, after 2 and 4 months of training, and 8 months after cessation of regular exercise. RESULTS-Training increased peak oxygen uptake (VO(2max)) by 13% after 2 months and by 27% after 4 months (P = 0.04). Flow-mediated dilation (FMD) of the brachial artery increased from 6.5 +/- 1.1 to 9.8 +/- 1.1% (P = 0.04) by training. L-NMMA administration decreased fundus pulsation amplitude (FPA) by 9.1 +/- 0.9% before training and by 13.4 +/- 1.5% after 4 months of training (P = 0.02). VO(2max), FMD, and FPA were unchanged in the control group. Vascular effects from training were abrogated 8 months after cessation of exercise. CONCLUSIONS-Our study demonstrates that aerobic exercise training can improve endothelial function in different vascular beds in patients with long-standing type 1 diabetes, who are at considerable risk for diabetic angiopathy. However, the beneficial effect on vascular function is not maintained in the absence of exercise.
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PMID:Exercise training improves vascular endothelial function in patients with type 1 diabetes. 1235 80


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