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)

N:-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural inhibitor of pluripotent hematopoietic stem cell entry into the S phase of the cell cycle and is normally present in human plasma. Ac-SDKP is exclusively hydrolyzed by ACE, and its plasma concentration is increased 5-fold after ACE inhibition in humans. We examined the effect of 0.05 to 100 nmol/L Ac-SDKP on 24-hour (3)H-thymidine incorporation (DNA synthesis) by cardiac fibroblasts both in the absence and presence of 5% FCS. Captopril (1 micromol/L) was added in all cases to prevent the degradation of Ac-SDKP. Treatment of cardiac fibroblasts with 5% FCS increased thymidine incorporation from a control value of 12 469+/-594 to 24 598+/-1051 cpm (P:<0.001). Cotreatment with 1 nmol/L Ac-SDKP reduced stimulation to control levels (10 373+/-200 cpm, P:<0.001). We measured hydroxyproline content and incorporation of (3)H-proline into collagenous fibroblast proteins and found that Ac-SDKP blocked endothelin-1 (10(-8) mol/L)-induced collagen synthesis in a biphasic and dose-dependent manner, causing inhibition at low doses, whereas high doses had little or no effect. It also blunted the activity of p44/p42 mitogen-activated protein kinase in a biphasic and dose-dependent manner in serum-stimulated fibroblasts, suggesting that the inhibitory effect of DNA and collagen synthesis may depend in part on blocking mitogen-activated protein kinase activity. Participation of p44/p42 in collagen synthesis was confirmed, because a specific inhibitor for p44/p42 activation (PD 98059, 25 micromol/L) was able to block endothelin-1-induced collagen synthesis, similar to the effect of Ac-SDKP. The fact that Ac-SDKP inhibits DNA and collagen synthesis in cardiac fibroblasts suggests that it may be an important endogenous regulator of fibroblast proliferation and collagen synthesis in the heart. Ac-SDKP may participate in the cardioprotective effect of ACE inhibitors by limiting fibroblast proliferation (and hence collagen production), and therefore it would reduce fibrosis in patients with hypertension.
Hypertension 2001 Mar
PMID:Effect of N-acetyl-seryl-aspartyl-lysyl-proline on DNA and collagen synthesis in rat cardiac fibroblasts. 1124 3

We evaluated the effects of cilnidipine, a long-acting Ca(2+) channel antagonist, on endothelial nitric oxide synthase (eNOS), preproendothelin-1 and endothelin ETA receptor expression in the left ventricle, and evaluated the relations between these effects and coronary microvascular remodeling and extracellular signal-regulated kinases belonging to one subfamily of mitogen-activated protein kinases in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Cilnidipine (DOCA-cilnidipine, 1 mg/kg/day, subdepressor dose) or vehicle (DOCA-vehicle) was given after induction of DOCA-salt hypertension for 5 weeks. The eNOS mRNA and protein expression in the left ventricle was significantly lower in DOCA-vehicle than in control rats and significantly higher in DOCA-cilnidipine than in DOCA-vehicle rats. Preproendothelin-1 and endothelin ETA receptor expression levels and phospho-p42/p44 extracellular signal-regulated kinase activities were significantly increased in DOCA-vehicle compared with control rats and significantly suppressed in DOCA-cilnidipine compared with DOCA-vehicle rats. DOCA-vehicle rats showed a significant increase in the wall-to-lumen ratio, perivascular fibrosis and myocardial fibrosis, with all these parameters being significantly improved by cilnidipine. These results led us to conclude that phospho-p42/p44 extracellular signal-regulated kinase activities may contribute to the coronary microvascular remodeling of DOCA rats and that protective effects of cilnidipine on cardiovascular remodeling may be at least in part mediated by an increased eNOS expression and a decreased endothelin-1 and endothelin ETA receptor expression in the left ventricle.
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PMID:Effects of cilnidipine on nitric oxide and endothelin-1 expression and extracellular signal-regulated kinase in hypertensive rats. 1143 Sep 25

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.
Hypertension 2001 Sep
PMID:Induction of B(1)-kinin receptors in vascular smooth muscle cells: cellular mechanisms of map kinase activation. 1156 39

The function of vascular endothelium as a biomechanical sensor permits alterations in gene expression in the vascular tree in response to wall stress. The present study explored the mechanism by which the arterial endothelium responds to changes in dietary salt. Normotensive rats were fed diets containing varying amounts of NaCl for 4 days. At that time, levels of phosphorylated p38 MAP kinase, p42/44 MAP kinase, and p46/54 JNK/SAP kinase increased when the diet contained > or = 3.0% NaCl. Kinase assays demonstrated dose-response relationships between dietary salt intake and the activities of p38 MAP kinase and p42/44 MAP kinase. Aortic segments from animals on the 8.0% NaCl diet produced greater amounts of total and active transforming growth factor-beta 1 (TGF-beta1) and nitric oxide. The MEK1 inhibitor, PD-098059, and the p38 MAP kinase inhibitor, SB-203580, decreased production of these bioactive compounds to background levels. Intravenous injection of tetraethylammonium chloride (TEA) into rats on the 8.0% NaCl diet decreased the activities of p38 MAP kinase and p42/44 MAP kinase, compared with rats on the same diet and given vehicle intravenously. These findings provided direct evidence that dietary salt modulated gene expression in the arterial wall through a tetraethylammonium-sensitive mechanism and activation of the p38 and p42/44 MAP kinase pathways.
Hypertension 2002 Feb
PMID:Increased dietary salt activates rat aortic endothelium. 1184 91

To better understand the intracellular signaling mechanism that causes the association of insulin resistance and hyperlipidemia with cardiovascular diseases, we specifically looked at the ability of lysophosphatidylcholine (lysoPC) to inhibit the Akt activation induced by insulin in cultured rat aortic vascular smooth muscle cells. LysoPC inhibited the insulin-induced phosphorylation of Akt at Ser473, and the inhibition was concentration dependent. Phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, inhibited the insulin-induced phosphorylation of Akt. LysoPC stimulated PKC phosphorylation at Ser660, which was inhibited by the PKC inhibitor GF109203X. The PKC-alpha/beta-selective inhibitor Go6976 also blocked the PMA- and lysoPC-induced inhibition of Akt phosphorylation by insulin. PKC-alpha, but not PKC-beta, is expressed in vascular smooth muscle cells, and overexpression of PKC-alpha, but not PKC-beta or PKC-delta, inhibited insulin-induced Akt activation. LysoPC rapidly stimulated PKC-alpha translocation to the membrane. In contrast, pretreatment with the p42/44 mitogen-activated protein kinase kinase inhibitor PD98059 or the p38 mitogen-activated protein kinase inhibitor SB203580 did not block the lysoPC-induced inhibition of Akt phosphorylation by insulin. In addition, lysoPC inhibited the insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 but not that of the insulin receptor beta subunit or insulin binding. PMA treatment or PKC-alpha overexpression also inhibited the tyrosine phosphorylation of IRS-1. From these data, we conclude that lysoPC negatively regulates the insulin signal at the point of IRS-1 through PKC-alpha in the vasculature, which may explain the association of hyperlipidemia with hyperinsulinemia in cardiovascular diseases.
Hypertension 2002 Feb
PMID:Lysophosphatidylcholine inhibits insulin-induced Akt activation through protein kinase C-alpha in vascular smooth muscle cells. 1188 99

A host of growth factors have been implicated in vascular pathologies; one such factor is heparin-binding epidermal growth factor-like growth factor (HB-EGF). Although HB-EGF has been shown to stimulate mitogenesis and chemotaxis of vascular smooth muscle cells (VSMC), its signaling mechanism remains undefined. In this study, we examined possible signal transduction pathways by which HB-EGF leads to mitogenesis in cultured rat VSMC. HB-EGF induced phosphorylation of the EGF receptor (EGFR) with maximum phosphorylation at 0.5 to 1 minute, whereas erbB4, the other receptor to which HB-EGF binds, was not activated on HB-EGF stimulation. HB-EGF induced a time- and concentration-dependent phosphorylation of mitogen-activated protein kinase (MAPK; p42/44 MAPK, extracellular signal-regulating kinase [ERK] 1/2). It also activated Akt and p70S6 kinase (p70S6K) but not p38 MAPK. HB-EGF-induced phosphorylation of these kinases was blocked by the EGFR kinase inhibitor AG1478. To investigate signaling molecules involved in HB-EGF-induced DNA synthesis, we pretreated VSMC with the specific ERK kinase mitogen-activated kinase (MEK) inhibitor PD98059 and the phosphatidylinositol 3-kinase inhibitor LY294002. These inhibitors significantly blocked HB-EGF-induced DNA synthesis. PD98059 inhibited HB-EGF-induced ERK activation, whereas it had no effect on Akt activation by HB-EGF. By contrast, LY294002 inhibited HB-EGF-induced Akt and p70S6K activation without effecting ERK activation by HB-EGF. These results demonstrate that HB-EGF-induced mitogenesis requires both ERK and phosphatidylinositol 3-kinase (Akt and p70S6K) pathways activated through EGFR, thereby providing a new mechanistic insight by which HB-EGF contributes to vascular remodeling.
Hypertension 2002 Feb
PMID:Signaling mechanisms of heparin-binding epidermal growth factor-like growth factor in vascular smooth muscle cells. 1188 2

Insulin resistance is an important risk factor in the development of cardiovascular diseases such as hypertension and atherosclerosis. However, the specific role of insulin resistance in the etiology of these diseases is poorly understood. Angiotensin (Ang) II is a potent vasculotrophic and vasoconstricting factor. We hypothesize that in vascular smooth muscle cells (VSMCs), Ang II interferes with insulin action by inhibiting Akt, a major signaling molecule implicated in the biological actions of insulin. By immunoblotting with a phospho-specific antibody for Akt, we found that Ang II inhibits insulin-induced Akt phosphorylation in a time- and concentration-dependent manner. The inhibitory effect of Ang II was blocked by a Ang II type 1 receptor antagonist, RNH6270. A protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate, also inhibited insulin-induced Akt phosphorylation. PKC inhibitors, including Go6976 (specific for alpha- and beta-isoforms), blocked the Ang II- and PMA-induced inhibition of Akt phosphorylation by insulin. Moreover, overexpression of PKC-alpha but not PKC-beta isoform by adenovirus inhibited insulin-induced Akt phosphorylation. By contrast, an epidermal growth factor receptor inhibitor (AG1478), a p42/44 mitogen-activated protein kinase (MAPK) kinase inhibitor (PD 598,059), and a p38 MAPK inhibitor (SB 203,580) did not block the Ang II-induced inhibition of Akt phosphorylation. From these data, we conclude that Ang II negatively regulates the insulin signal, Akt, in the vasculature specifically through PKC-alpha activation, providing an alternative molecular mechanism that may explain the association of hyperinsulinemia with cardiovascular diseases.
Hypertension 2003 Mar
PMID:Insulin-induced Akt activation is inhibited by angiotensin II in the vasculature through protein kinase C-alpha. 1262 95

Endothelin (ET), derived from the endothelium of blood vessels, is a potent vasoactive peptide. Although it has been reported to be involved in cardiovascular diseases, such as hypertension, the mechanism by which ET evokes vasoconstriction is still unclear. On the other hand, p42/p44 mitogen-activated protein kinase (MAPK) and p38 MAPK are activated by a variety of growth factors and cellular stresses, respectively. However, the role of p42/p44 MAPK and p38 MAPK on the ET-1-induced vasoconstriction is not fully understood. This study was undertaken to determine whether p42/p44 MAPK and p38 MAPK participate in the regulation of vascular smooth muscle contraction by ET-1. The isometric vasoconstriction and intracellular Ca(2+) ([Ca(2+)](i)) were simultaneously measured using CAF-100. Phosphorylation of myosin light chain (MLC) and p42/p44 MAPK, p38 MAPK were determined by Western blots. In rat thoracic aorta, ET-1 induced a sustained contraction. In contrast, [Ca(2+)](i) was decreased with time. Both PD98059, an inhibitor of p42/p44 MAPK, and SB203580, an inhibitor of p38 MAPK, partially attenuated ET-1-induced contractions in concentration-dependent manners. ET-1 increased phosphorylation of both p42/p44 MAPK and p38 MAPK, and PD98059 and SB203580 completely decreased phosphorylation of p42/p44 MAPK and p38 MAPK in response to ET-1 stimulation, respectively. On the other hand, PD98059 and SB203580 did not affect MLC phosphorylation in response to ET-1 stimulation. These results indicate that p38 MAPK, as well as p42/p44 MAPK, may partially regulate the ET-1-induced contraction through a MLC phosphorylation-independent pathway.
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PMID:Mitogen-activated protein kinases partially regulate endothelin-1-induced contractions through a myosin light chain phosphorylation-independent pathway. 1265 18

The study of salt-sensitive hypertension has been facilitated by development of genetic models, especially the Dahl/Rapp salt-sensitive (S) rat. S rats rapidly become hypertensive after initiation of a diet containing 8.0% NaCl and subsequently develop arteriolonephrosclerosis and renal failure, whereas the salt-resistant (R) strain remains normotensive on the same diet. The purpose of the present study was to use these strains to demonstrate the interactions between transforming growth factor-beta1 (TGF-beta1) and nitric oxide (NO). Young, male S and R rats were fed for 4 days diets that contained either 0.3 or 8.0% NaCl. An increase in dietary salt increased kinase activities of both p38 MAPK and p42/44 MAPK in cytoplasmic extracts from aortic rings and isolated glomeruli from both strains. Inhibition of either pathway with PD-098059 or SB-203580 decreased production of TGF-beta1 and nitrate plus nitrite (NOx). In both strains, production of active TGF-beta1 and NOx linearly correlated. Incubation of aortic rings and isolated glomeruli with the NO donor NOR3 decreased TGF-beta1 levels, whereas the NO synthase inhibitor Nomega-nitro-l-arginine methyl ester increased production. The inhibitory effect of NO on production of TGF-beta1 was reduced in preparations from S rats. Although a close interrelationship existed between TGF-beta1 and NO in both strains, production of TGF-beta1 was increased in prehypertensive S rats and was further exaggerated with the increase in dietary salt intake. Augmented vascular and glomerular production of TGF-beta1 and diminished NO may contribute to the development of hypertensive nephrosclerosis in S rats.
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PMID:The interrelationship between TGF-beta1 and nitric oxide is altered in salt-sensitive hypertension. 1286 56

Vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species play critical roles in early atherogenesis, and nitric oxide (NO) is an important regulator of the cardiovascular system. Although celiprolol, a specific beta1-antagonist with weak beta2-agonistic action, stimulates endothelial nitric oxide synthase (eNOS) production, the mechanisms remain to be determined. Because it was recently reported that phosphatidylinositol 3-kinase (PI3K) and its downstream effector Akt are implicated in the activation of eNOS and that regulation of VCAM-1 expression is mediated via nuclear factor-kappaB (NF-kappaB), we hypothesized that celiprolol activates phosphorylation of eNOS through the PI3K-Akt signaling pathway; that celiprolol modulates VCAM-1 expression, which is associated with inhibiting NF-kappaB phosphorylation; and that celiprolol suppresses NAD(P)H oxidase p22phox, p47phox, gp91phox, and nox1 expression in the left ventricle of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. eNOS and Akt phosphorylation upregulated by celiprolol alone were suppressed by treatment with celiprolol plus wortmannin. Increased expression of VCAM-1, p22phox, p47phox, gp91phox, nox1, activated p65 NF-kappaB, c-Src, p44/p42 extracellular signal-regulated kinases, and their downstream effector p90 ribosomal S6 kinase phosphorylation in DOCA rats was inhibited by celiprolol. Celiprolol administration resulted in a significant improvement in cardiovascular remodeling and suppression of transforming growth factor-beta1 gene expression. In conclusion, celiprolol suppresses VCAM-1 expression because of inhibition of oxidative stress, NF-kappaB, and signal transduction, while increasing eNOS via stimulation of the PI3K-Akt signaling pathway and improving cardiovascular remodeling.
Hypertension 2003 Nov
PMID:Celiprolol activates eNOS through the PI3K-Akt pathway and inhibits VCAM-1 Via NF-kappaB induced by oxidative stress. 1455 79


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