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

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional cytokine capable of regulating the growth and differentiation of many cell types, as well as regulating their environment in the blood vessel wall. Its production by endothelium and/or vascular smooth muscle is stimulated by biophysical forces, growth factors and also vasoconstrictors. In hypertension TGF-beta 1 gene transcription is most likely elevated by a combination of physical and chemical stimuli with the cytokine acting to increase the production of extracellular matrix proteins or to modulate smooth muscle cellular growth, producing hypertrophy, polyploidy or proliferation. With respect to the latter, TGF-beta 1 potentiates the proliferative effects of many receptor tyrosine kinase-activating growth factors in vascular smooth muscle from SHR, but inhibits such proliferation in WKY smooth muscle. It also differentially affects collagen production by the two cell types. It is suggested that the augmented proliferative response in renal hypertensive SHR, compared to renal hypertensive WKY, is the consequence of these differential effects of TGF-beta 1 on smooth muscle cell proliferation. TGF-beta 1 is also likely to be a significant contributor to the development of vascular hypertrophy in genetic hypertension.
 ...
PMID:Transforming growth factor-beta 1 and the development of vascular hypertrophy in hypertension. 758 73

Tyrosine kinases have been implicated in vascular smooth muscle cell proliferation and contraction. Underlying mechanisms may involve C(a2+) -dependent pathways. This study assesses relationships between angiotensin II (Ang II)-stimulated phospholipase C-mediated Ca2+ transients and tyrosine kinase-dependent pathways in vascular smooth muscle cells. Intracellular free Ca2+ concentration ([Ca2+]i) was measured in primary cultured unpassaged vascular smooth muscle cells derived from mesenteric resistance vessels of Wistar-Kyoto rats with the use of fura 2 methodology. [Ca2+]i effects of Ang II (1 nmol/L) were determined in vascular smooth muscle cells in which tyrosine kinase pathways were stimulated by insulin (70 muU/mL; 0.5 nmol/L), insulin-like growth factor-I (1 ng/mL; 0.13 nmol/L), or platelet-derived growth factor-BB (1 ng/mL; 0.04 nmol/L) and in cells in which tyrosine kinase was inhibited by specific inhibitors (1 mumol/L tyrphostin A-23 and genistein). Ang II elicited a rapid and transient [Ca2+]i response (from 94 +/- 8 to 239 +/- 5.8 nmol/L). Activation of the receptor tyrosine kinase by insulin, platelet-derived growth factor, and insulin-like growth factor-I significantly reduced (P < .01) Ang II-induced [Ca2+]i to 161 +/- 7, 189 +/- 3.7, and 183 +/- 5 nmol/L, respectively. In the presence of tyrphostin A-23 and genistein, Ang II-stimulated [Ca2+]i remained persistently elevated and failed to return to basal levels. Tyrphostin A-1, the inactive tyrphostin analogue, had not significant effect on Ang II-induced [Ca2+]i. This study demonstrates that activation of tyrosine kinase pathways reduces Ang II-elicited [Ca2+]i responses, whereas tyrosine kinase inhibition prevents [Ca2+]i recovery after agonist stimulation. Interaction between tyrosine kinase- and phospholipase C-dependent signaling pathways modulates vascular smooth muscle cell [Ca2+]i responses to Ang II.
Hypertension 1996 May
PMID:Tyrosine kinase signaling pathways modulate angiotensin II-induced calcium ([Ca2+]i) transients in vascular smooth muscle cells. 862 Dec 2

Vascular smooth muscle cells of rat aorta express imidazoline receptors whose stimulation, by drugs or an endogenous ligand, agmatine, inhibits serum-stimulated proliferation. We investigated whether imidazoline receptors are expressed in human vascular smooth muscle cells if their stimulation is antiproliferative. Cultured human coronary artery vascular smooth muscle cells express a nonadrenergic binding site for 3H-idazoxan and an imidazoline receptor-binding protein as revealed by immunocytochemical and immunoblot analyses with a specific antibody. Idazoxan and agmatine dose-dependently inhibited serum-stimulated proliferation of these cells as measured by the incorporation of 3H-thymidine (IC50: 5 and 70 micromol/L, respectively) and serum-stimulated expression of proliferating cell nuclear antigen and cell numbers. The agents inhibited proliferation of human and rat (aorta) smooth muscle cells stimulated by either norepinephrine (6560+/-440 disintegrations per minute norepinephrine versus 3345+/-220 norepinephrine and idazoxan), angiotensin II (7680+/-335 disintegrations per minute angiotensin II versus 3769+/-450 angiotensin II and idazoxan), or platelet-derived growth factor (IC50: 3 micromol/L for idazoxan and 40 micromol/L for agmatine), indicating inhibition of mitosis mediated by G-protein or receptor tyrosine kinase pathways. We conclude that human vascular smooth muscle cells express imidazoline-receptors whose activation inhibits proliferation by interacting at a distal step in an intracellular signal cascade common to G-protein and receptor tyrosine kinase mitogenic pathways. Agmatine, synthesized in endothelium, may act as a paracrine regulator of vascular smooth muscle cell proliferation through imidazoline receptors, and agents acting at this site may be useful in treating vascular hyperplasia.
Hypertension 1997 Aug
PMID:Stimulation of imidazoline receptors inhibits proliferation of human coronary artery vascular smooth muscle cells. 926 Sep 95

Lowering of tumor interstitial hypertension, which acts as a barrier for tumor transvascular transport, has been proposed as a general strategy to enhance tumor uptake and therapeutic effects of anticancer drugs. The tyrosine kinase platelet-derived growth factor (PDGF) beta-receptor is one mediator of tumor hypertension. The effects of PDGF antagonists on chemotherapy response were investigated in two tumor models that display PDGF receptor expression restricted to the tumor stroma, and in which PDGF antagonists relieve tumor hypertension. Inhibitory PDGF aptamers and the PDGF receptor tyrosine kinase inhibitor STI571 enhanced the antitumor effect of Taxol on s.c. KAT-4 tumors in SCID mice. Treatment with only PDGF antagonists had no effect on tumor growth. Taxol uptake in tumors was increased by treatment with PDGF antagonists. Cotreatment with PDGF antagonists and Taxol was not associated with antiangiogenic effects, and PDGF antagonists did not enhance the Taxol effect on in vitro growth of KAT-4 cells. STI571 also increased the antitumor effects of 5-fluorouracil on s.c. PROb tumors in syngeneic BDIX rats, without increasing the effect of 5-fluorouracil on cultured PROb cells. Expression of PDGF receptors in tumor stroma, as well as tumor hypertension, occurs in most common solid tumors. Therefore, our results have implications for treatment regimens for large patient groups and merit clinical testing. In conclusion, our study identifies inhibition of PDGF signaling in tumor stroma as a novel, possibly general strategy for enhancement of the therapeutic effects chemotherapy.
 ...
PMID:Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. 1235 56

Extracellular signal-regulated kinase 1/2 (ERK1/2) may play a central signaling role in vascular remodeling. We investigated a possible combined role for the renin-angiotensin system and platelet-derived growth factor beta-receptor (PDGF-beta-R) in pressure-induced ERK1/2 activation in intact rat mesenteric small arteries. In an organ culture model, vessels were pressurized (70 mm Hg) for 1 hour plus a 5-minute intervention period. The intervention was either a rise in intraluminal pressure (up to 140 mm Hg) or challenge with angiotensin II (Ang II, 0.1 micromol/L) or PDGF-BB (30 microg/L). ERK1/2 activation was determined by Western blotting as formation of phosphorylated ERK1/2. All interventions caused ERK1/2 activation that was inhibited by the MEK inhibitor PD98059. The response to pressure was inhibited by an ACE inhibitor (perindoprilat), an Ang II receptor type 1 (R-AT1) antagonist (candesartan), and tyrosine kinase inhibitors (genistein, herbimycin A). An R-AT2 antagonist (PD123319) had no significant effect. Both a PDGF-receptor tyrosine kinase inhibitor (RPR101511A) and a neutralizing PDGF-beta-R antibody (AF385) inhibited the activation of ERK1/2 caused by PDGF-BB, Ang II, and pressure. That the latter interventions could indeed inhibit the PDGF-beta-R was supported by experiments with unmounted vessels in which PDGF-beta-R activation was measured by Western blot; both PDGF-BB and Ang II-mediated PDGF-beta-R activation were inhibited by RPR101511A and AF385. Immunohistochemistry showed that ERK1/2 and PDGF-beta-R was located in the adventitia, tunica media, and intima. The results suggest that pressure in rat mesenteric small arteries causes acute activation of ERK1/2 through pathways involving Ang II and PDGF-beta-R.
Hypertension 2003 Apr
PMID:Pressure-induced activation of extracellular signal-regulated kinase 1/2 in small arteries. 1262 63

Phosphoinositide-3 kinases (PI3Ks) are a family of evolutionary conserved lipid kinases that mediate many cellular responses in both physiologic and pathophysiologic states. Class I PI3K can be activated by either receptor tyrosine kinase (RTK)/cytokine receptor activation (class I(A)) or G-protein-coupled receptors (GPCR) (class I(B)). Once activated PI3Ks generate phosphatidylinositols (PtdIns) (3,4,5)P(3) leading to the recruitment and activation of Akt/protein kinase B (PKB), PDK1 and monomeric G-proteins (e.g. Rac-GTPases), which then activate a range of downstream targets including glycogen synthase kinase-3beta (GSK-3beta), mammalian target of rapamycin (mTOR), p70S6 kinase, endothelial nitric oxide synthase (eNOS) and several anti-apoptotic effectors. Class I(A) (PI3Kalpha, beta and delta) and class I(B) (PI3Kgamma) PI3Ks mediate distinct phenotypes in the heart and under negative control by the 3'-lipid phosphatase, phosphatase and tensin homolog on chromosome ten (PTEN) which dephosphorylate PtdIns(3,4,5)P(3) into PtdIns(4,5)P(2). PI3Kalpha, gamma and PTEN are expressed in cardiomyocytes, fibroblasts, endothelial cells and vascular smooth muscle cells where they modulate cell survival/apoptosis, hypertrophy, contractility, metabolism and mechanotransduction. Several transgenic and knockout models support a fundamental role of PI3K/PTEN signaling in the regulation of myocardial contractility and hypertrophy. Consequently the PI3K/PTEN signaling pathways are involved in a wide variety of diseases including cardiac hypertrophy, heart failure, preconditioning and hypertension. In this review, we discuss the biochemistry and molecular biology of PI3K (class I isoforms) and PTEN and their critical role in cardiovascular physiology and diseases.
 ...
PMID:The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. 1527 15

The renin-ANG system has been reported to be overexpressed in pulmonary arterial hypertension (PAH). We investigated the effects of ANG receptor-1 blockade by losartan on hemodynamics and signaling molecules in a piglet overflow model of early PAH. Twenty-six 3-wk-old piglets were randomized to placebo or losartan therapy (1 mg.kg(-1).day(-1)) after anastomosis of the inominate to the main pulmonary artery or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative-PCR. Chronic systemic-to-pulmonary shunting increased the pulmonary vascular resistance from 2.5 +/- 0.2 to 6.2 +/- 0.3 mmHg.l(-1).min.m(-2) and arteriolar medial thickness from 13.6 to 25.4%. These changes were associated with increased expressions of ANG II and its type 1 (AT1) and type 2 (AT2) receptors, endothelin-1 (ET-1) and its type B receptor (ETB), and angiopoietin-1, together with decreased expressions of bone morphogeneic protein receptor-1A and -2 (BMPR-1A and BMPR-2, respectively) and unchanged expression of the receptor tyrosine kinase with immunoglobulin and EGF homology domains-2 (Tie 2). Pretreatment with losartan decreased shunt-induced pulmonary vascular resistance and medial thickness by 51% and 35%, respectively. Losartan therapy was associated with persistent overexpressions of ANG II, AT2, ET-1, ETB, and angiopoietin-1 and with a return to normal of the BMPR-2 expression. These results suggest that ANG II contributes to left-to-right, shunt-induced PAH.
 ...
PMID:Prevention of pulmonary vascular remodeling and of decreased BMPR-2 expression by losartan therapy in shunt-induced pulmonary hypertension. 1602 66

Imatinib specifically inhibits receptor tyrosine kinase signaling and is clinically used to treat leukemia. Receptor tyrosine kinases not only mediate tumor growth but also initiate adverse signaling in heart failure. We investigated whether imatinib, by inhibiting the platelet-derived growth factor receptor-beta (PDGFRbeta), prevents cardiac and renal damage in TGR(mRen2)27 (Ren2) rats. Eight-week-old male homozygous Ren2 and Sprague Dawley rats were treated either with imatinib (30 mg/kg; STI-571) or placebo for 8 weeks (Ren2 n=12 for each group; Sprague Dawley n=6 for each group). Imatinib did not affect blood pressure or left ventricular (LV) hypertrophy in both groups. Imatinib attenuated the decline in fractional shortening (imatinib versus Ren2 placebo 45+/-4.5% versus 32+/-3%; n=7-11; P<0.05) and in diastolic function in Ren2 rats (baseline diastolic dP/dt corrected for systolic blood pressure Ren2 imatinib versus Ren2 placebo 38.6+/-0.67 versus 35.3+/-0.41 [1 . s(-1)]; n=7-11; P<0.05). This was associated with decreased cardiac fibrosis and decreased activation of PDGFRbeta and extracellular signal-regulated kinase 1/2. Renal microvascular hypertrophy and perivascular fibrosis in Ren2 rats were significantly decreased by imatinib. In vitro, imatinib blocked angiotensin II-induced activation of the PDGFRbeta and significantly decreased fibroblast proliferation and collagen production. In conclusion, imatinib did not affect LV hypertrophy but attenuated the decline in cardiac function and reduced renal microvascular damage associated with reduced activation of the PDGFRbeta. The simultaneous improvement in both heart and kidneys suggests that inhibition of the PDGFRbeta has broad protective effects that may provide novel avenues for a blood pressure-independent protection against end-organ damage.
Hypertension 2006 Mar
PMID:Imatinib attenuates end-organ damage in hypertensive homozygous TGR(mRen2)27 rats. 1643 51

The abnormal proliferation of aortic vascular smooth muscle cells (VSMCs) plays a central role in the pathogenesis of atherosclerosis and restenosis after angioplasty and possibly also in the development of hypertension. The present study was designed to examine the inhibitory effects and the mechanism of luteolin 7-glucoside (L7G) on the platelet-derived growth factor (PDGF)-BB-induced proliferation of VSMCs. L7G significantly inhibited the PDGF-BB-induced proliferation and the DNA synthesis of the VSMCs in a concentration-dependent manner. Pre-incubation of the VSMCs with L7G significantly inhibited the PDGF-BB-induced extracellular signal-regulated kinase 1/2 (ERK1/2), Akt and the phospholipase C (PLC)-gamma1 activation. However, L7G had almost no affect on the phosphorylation of PDGF-beta receptor tyrosine kinase, which was induced by PDGF-BB. These results suggest that L7G inhibits the PDGF-BB-induced proliferation of VSMCs via the blocking of PLC-gamma1, Akt, and ERK1/2 phosphorylation.
 ...
PMID:The inhibitory effect and mechanism of luteolin 7-glucoside on rat aortic vascular smooth muscle cell proliferation. 1649 46

Atherosclerosis is the underlying pathology of most cardiovascular disease and it represents the major cause of premature death in modern societies. Current therapies target risk factors being hypertension, hypercholesterolemia, hypertriglyceridemia and hyperglycemia when diabetes is present however the maximum efficacy of these strategies is often 30% or less. Areas of vascular biology that may lead to the development of a complementary vascular wall directed therapy are: inflammation, oxidation, endothelial dysfunction, diabetes-specific factors--hyperglycemia and advanced glycation endproducts and lipid retention by vascular matrix specifically proteoglycans. The major structural features of proteoglycans that determine low-density lipoprotein (LDL) binding are the length and sulfation pattern on the glycosaminoglycan (GAG) chains. Emerging data discussed in this review indicates that these structural properties are subject to considerable regulation by vasoactive substances possibly using novel signaling pathways. For example, GAG elongation stimulated by platelet-derived growth factor is not blocked by the receptor tyrosine kinase antagonist, genistein suggesting that there may be a previously unknown signaling pathway involved in this response. Thus, modifying proteoglycan synthesis and structure may represent a prime target to prevent LDL binding and entrapment in the vessel wall and thus prevent the development and progression of atherosclerosis.
 ...
PMID:Vascular wall proteoglycan synthesis and structure as a target for the prevention of atherosclerosis. 1758 82


1 2 3 4 5 6 7 Next >>