Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In addition to well-documented vascular growth-promoting effects, ANG II exerts proapoptotic effects that are poorly understood. IGF-1 is a potent survival factor for human vascular smooth muscle cells (hVSMC), and its antiapoptotic effects are mediated via the IGF-1 receptor (IGF-1R) through a signaling pathway involving phosphatidylinositol 3-kinase and Akt. We hypothesized that there would be cross talk between ANG II proapoptotic effects and IGF-1 survival effects in hVSMC. To investigate ANG II-induced apoptosis and the potential involvement of IGF-1, we exposed quiescent and nonquiescent hVSMC to ANG II. ANG II induced apoptosis only in nonquiescent cells but stimulated hypertrophy in quiescent cells. ANG II-induced apoptosis was characterized by marked inhibition of Akt phosphorylation and stimulation of membrane Fas ligand (FasL) expression, caspase-8 activation, and a reduction in soluble FasL expression. Adenovirally mediated overexpression of Akt rescued hVSMC from ANG II-induced apoptosis. IGF-1R activation increased Akt phosphorylation and soluble FasL expression, and these effects were completely blocked by coincubating hVSMC with ANG II. In conclusion, ANG II-induced apoptosis of hVSMC is characterized by marked inhibition of Akt phosphorylation and stimulation of an extrinsic cell death signaling pathway via upregulation of membrane FasL expression, caspase-8 activation, and a reduction in soluble FasL expression. Furthermore, ANG II antagonizes the antiapoptotic effect of IGF-1 by blocking its ability to increase Akt phosphorylation and soluble FasL. These findings provide novel insights into ANG II-induced apoptotic signaling and have significant implication for understanding ANG II-induced remodeling in hypertension and atherosclerosis.
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PMID:ANG II induces apoptosis of human vascular smooth muscle via extrinsic pathway involving inhibition of Akt phosphorylation and increased FasL expression. 1633 40

It is hypothesized that preeclampsia is caused by factors from the placenta that induce endothelial cell activation. Trophoblasts are cells that may be shed from the placenta, then deported in the maternal blood, and finally become trapped in the pulmonary capillaries. The ultimate fate of deported trophoblasts is unknown, but to prevent clogging of the pulmonary circulation they must be cleared from the capillary beds. We examined the hypothesis that endothelial cells phagocytose deported trophoblasts and also examined the consequent effects of the trophoblasts on endothelial cells. Fluorescently labeled trophoblast-derived choriocarcinoma cells were induced to become apoptotic or necrotic and exposed to endothelial cell monolayers. Confocal microscopy demonstrated uptake of both apoptotic and necrotic trophoblasts, and this phagocytosis could be inhibited by cytochalasin B. Phagocytosis of necrotic but not apoptotic trophoblasts induced increased endothelial intercellular adhesion molecule 1 (ICAM-1) expression, as well as increased adhesion of monocytes to endothelial cell monolayers. Inhibiting the phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase pathways blocked both expression of ICAM-1 and phagocytosis, whereas inhibition of the P42/44 mitogen-activated protein kinase pathway blocked only ICAM-1 expression. This work suggests that endothelial cells can phagocytose deported trophoblasts and that the mechanism of trophoblast death (apoptotic or necrotic) could have major effects on the maternal vascular response to shed trophoblasts.
Hypertension 2006 Jan
PMID:Phagocytosis of necrotic but not apoptotic trophoblasts induces endothelial cell activation. 1634 69

Angiotensin (Ang) II is implicated in hypertension, vascular remodeling, and insulin resistance. Peroxisome proliferator-activated receptor (PPAR) gamma activators increase insulin sensitivity and improve Ang II-induced vascular remodeling. We evaluated the effects of the PPAR-gamma activator rosiglitazone on Ang II signaling in aorta and mesenteric arteries. Rats received Ang II by subcutaneous infusion and/or rosiglitazone per os for 7 days. Blood pressure rise in Ang II-infused rats was attenuated by rosiglitazone. Ang II significantly increased Ang II type 1 receptor expression in the mesenteric arteries (P<0.001), whereas that of the aorta was decreased (P<0.05), changes which were reversed by rosiglitazone. Akt activity was increased by Ang II and returned to basal levels under rosiglitazone in both vascular beds. However, Ang II-induced extracellular signal-regulated kinase 1/2 activity increased in aorta but not in mesenteric vessels (P<0.001), where 4E-binding protein 1 activity was significantly increased by Ang II and inhibited by PPAR-gamma activation. In response to Ang II, Src homology (SH) 2-containing inositol phosphatase 2 activity was increased (P<0.05) in both vascular beds. In conclusion, PPAR-gamma activator rosiglitazone attenuated Ang II-induced blood pressure elevation and intracellular signaling on aorta and mesenteric vessels. There was differential inhibition of Ang II type 1 receptor receptors/phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase 1/2 in both vessels. Effects of PPAR-gamma activators on these pathways could contribute to regression of vascular remodeling in models of hypertension and diabetes and, accordingly, in hypertensive diabetic patients.
Hypertension 2006 Jan
PMID:Peroxisome proliferator-activated receptor gamma regulates angiotensin II-stimulated phosphatidylinositol 3-kinase and mitogen-activated protein kinase in blood vessels in vivo. 1634 71

The functional impairment associated with atherogenic factors, including hypertension, constitutes a limitation to the ability of endothelial progenitor cells (EPCs) to repair. In addition, estrogens have been shown to play a role in reendothelialization after vascular injury. We investigated the effects of estrogens on differentiation and senescence of EPCs derived from bone marrow (BM-EPCs) in spontaneously hypertensive rats (SHR/Izm). Bone marrow (BM) cells were obtained from the tibias and femurs of age-matched, male SHR/Izm and Wistar-Kyoto rats (WKY/Izm). The number of differentiated, adherent BM-EPCs derived from SHR/Izm was significantly smaller than the number derived from WKY/Izm. 17beta-Estradiol (E2) significantly increased the number of adherent BM-EPCs from SHR/Izm, and this effect was significantly attenuated by pharmacological phosphatidylinositol 3-kinase (PI3-K) blockers. Immunoblotting analysis revealed that E2 treatment led to phosphorylation of Akt. Senescence, as assessed by acidic beta-galactosidase staining, occurred at a significantly greater rate in the BM-EPCs from SHR/Izm than in those from WKY/Izm, but E2 treatment dramatically delayed the senescence of BM-EPCs from SHR/Izm. A polymerase chain reaction (PCR)-ELISA based assay revealed that telomerase activity in BM-EPCs from SHR/Izm was significantly lower than in those from WKY/Izm, but that E2 treatment significantly augmented it. Both MTS and colony forming unit assay revealed that E2 treatment significantly augmented the functional activity in BM-endothelial cell (EC)-like cells from SHR/Izm compared to that in control BM-EC-like cells (no treatment). In conclusion, the differentiation of BM-EPCs derived from SHR/Izm was significantly decreased compared with that of BM-EPCs from WKY/Izm. In addition, the rate of senescence was significantly greater in the BM-EPCs from SHR/Izm than in those from WKY/Izm. Estrogen was shown to augment differentiation and delay the onset of senescence in BM-EPCs from SHR/Izm.
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PMID:Effect of estrogen on differentiation and senescence in endothelial progenitor cells derived from bone marrow in spontaneously hypertensive rats. 1641 50

The stress-responsive serum- and glucocorticoid-inducible kinase Sgk-1 is involved in osmoregulation and cell survival and may contribute to fibrosis and hypertension. However, the function of Sgk-1 in vascular remodeling and thrombosis, 2 major determinants of pulmonary hypertension (PH), has not been elucidated. We investigated the role of Sgk-1 in thrombin signaling and tissue factor (TF) expression and activity in pulmonary artery smooth muscle cells (PASMC). Thrombin increased Sgk-1 activity and mRNA and protein expression. H2O2 similarly induced Sgk-1 expression. Antioxidants, dominant-negative Rac, and depletion of the NADPH oxidase subunit p22phox diminished thrombin-induced Sgk-1 expression. Inhibition of p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and phosphoinositide-dependent kinase-1 prevented thrombin-induced Sgk-1 expression. Thrombin or Sgk-1 overexpression enhanced TF expression and procoagulant activity, whereas TF upregulation by thrombin was diminished by kinase-deficient Sgk-1 and was not detectable in fibroblasts from mice deficient in sgk-1 (sgk1(-/-)). Similarly, dexamethasone treatment failed to induce TF expression and activity in lung tissue from sgk1(-/-) mice. Transcriptional induction of TF by Sgk-1 was mediated through nuclear factor kappaB. Finally, Sgk-1 and TF proteins were detected in the media of remodeled pulmonary vessels associated with PH. These data show that thrombin potently induces Sgk-1 involving NADPH oxidases, phosphatidylinositol 3-kinase, p38 mitogen-activated protein kinase, and phosphoinositide-dependent kinase-1, and that activation of nuclear factor kappaB by Sgk-1 mediates TF expression and activity by thrombin. Because enhanced procoagulant activity can promote pulmonary vascular remodeling, and Sgk-1 and TF were present in the media of remodeled pulmonary vessels, this pathway may play a critical role in vascular remodeling in PH.
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PMID:The serum- and glucocorticoid-inducible kinase Sgk-1 is involved in pulmonary vascular remodeling: role in redox-sensitive regulation of tissue factor by thrombin. 1648 15

We have demonstrated that insulin stimulates sodium reabsorption in the distal nephron by stimulating the phosphatidylinositol 3-kinase (PI 3-kinase) pathway and that any stimulation of this enzyme (e.g. by EGF, by H2O2 or by exogenous PIP3, added apically) leads to a parallel increase in sodium reabsorption. We therefore suggest that hyperinsulinemia leads to hypertension through increased renal sodium reabsorption in the distal nephron.
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PMID:[Insulin and arterial hypertension: the role of the kidney]. 1650 70

Endothelial dysfunction contributes to cardiovascular diseases, including hypertension, atherosclerosis, and coronary artery disease, which are also characterized by insulin resistance. Insulin resistance is a hallmark of metabolic disorders, including type 2 diabetes mellitus and obesity, which are also characterized by endothelial dysfunction. Metabolic actions of insulin to promote glucose disposal are augmented by vascular actions of insulin in endothelium to stimulate production of the vasodilator nitric oxide (NO). Indeed, NO-dependent increases in blood flow to skeletal muscle account for 25% to 40% of the increase in glucose uptake in response to insulin stimulation. Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways in endothelium related to production of NO share striking similarities with metabolic pathways in skeletal muscle that promote glucose uptake. Other distinct nonmetabolic branches of insulin-signaling pathways regulate secretion of the vasoconstrictor endothelin-1 in endothelium. Metabolic insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling, which in endothelium may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Therapeutic interventions in animal models and human studies have demonstrated that improving endothelial function ameliorates insulin resistance, whereas improving insulin sensitivity ameliorates endothelial dysfunction. Taken together, cellular, physiological, clinical, and epidemiological studies strongly support a reciprocal relationship between endothelial dysfunction and insulin resistance that helps to link cardiovascular and metabolic diseases. In the present review, we discuss pathophysiological mechanisms, including inflammatory processes, that couple endothelial dysfunction with insulin resistance and emphasize important therapeutic implications.
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PMID:Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. 1661 33

Nonesterified fatty acids are acutely liberated during lipolysis and are chronically elevated in pathological conditions such as insulin resistance, hypertension, and obesity, which are known risk factors for atherosclerosis. The present study was designed to investigate the effects of oleic acid (OA), an 18-carbon cis-monosaturated fatty acid on proliferation of vascular smooth muscle cells (VSMC). Incubation of a rat VSMC (A10 cells) with OA (50 microM) resulted in an increase of cells entering the S phase of the cell cycle. In consistent with the effects on cell cycle distribution, OA stimulated VSMC proliferation in a dose-dependent manner. The mitogenic effect of OA was significantly reduced by pretreatment of LY294002 (5 microM) or wortmannin (1 microM), potent, and specific inhibitors of phosphatidylinositol 3-kinase (PI3K). OA also induced activation of Akt/protein kinase B (PKB) in a time-dependent manner. OA-induced activation of Akt/PKB was inhibited by either LY294002 or wortmannin. Taken together, these experiments show that the enhanced phosphorylation of Akt/PKB by OA is dependent on PI3K and suggest that this signaling event may be important for the regulation of OA-induced VSMC proliferation.
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PMID:Oleic acid enhances vascular smooth muscle cell proliferation via phosphatidylinositol 3-kinase/Akt signaling pathway. 1662 93

Insulin resistance has been described in several diseases that increase cardiovascular risk and mortality, such as diabetes, obesity, hypertension, metabolic syndrome, and heart failure. Abnormalities of insulin signaling account for insulin resistance. Insulin mediates its action on target organs through phosphorylation of a transmembrane-spanning tyrosine kinase receptor, the insulin receptor (IR). Several mechanisms have been described as responsible for the inhibition of insulin-stimulated tyrosine phosphorylation of IR and the IR substrate (IRS) proteins, including proteasome-mediated degradation, phosphatase-mediated dephosphorylation, and kinase-mediated serine/threonine phosphorylation. In particular, phosphorylation of IRS-1 on serine Ser612 causes dissociation of the p85 subunit of phosphatidylinositol 3-kinase, inhibiting further signaling. On the other hand, phosphorylation of IRS-1 on Ser307 results in its dissociation from the IR and triggers proteasome-dependent degradation. Dysregulation of sympathetic nervous and renin-angiotensin systems resulting in enhanced stimulation of both adrenergic and angiotensin II receptors is a typical feature of several cardiovascular diseases and, at the same time, is involved in the pathogenesis of insulin resistance. The characterization of molecular mechanisms involved in the pathogenesis of insulin resistance may help to design efficacious pharmacologic molecules to treat endothelial and metabolic dysfunction associated with insulin resistance states to reduce the cardiovascular risk and to ameliorate the prognosis of patients with cardiovascular diseases.
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PMID:Insulin resistance and cardiovascular risk: New insights from molecular and cellular biology. 1683 60

Plasma free fatty acid (FFA) levels are elevated in obesity. FFA, by causing insulin resistance in muscle, liver, and endothelial cells, contributes to the development of type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD). The mechanism through which FFA induces insulin resistance involves intramyocellular and intrahepatocellular accumulation of triglycerides and diacylglycerol, activation of several serine/threonine kinases, reduction in tyrosine phosphorylation of the insulin receptor substrate (IRS)-1/2, and impairment of the IRS/phosphatidylinositol 3-kinase pathway of insulin signaling. FFA also produces low-grade inflammation in skeletal muscle and liver through activation of nuclear factor-kappaB, resulting in release of several proinflammatory and proatherogenic cytokines. Thus, elevated FFA levels (due to obesity or to high-fat feeding) cause insulin resistance in skeletal muscle and liver, which contributes to the development of T2DM, and produce low-grade inflammation, which contributes to the development of atherosclerotic vascular diseases and NAFLD.
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PMID:Fatty acid-induced inflammation and insulin resistance in skeletal muscle and liver. 1689 68


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