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)

The type I cGMP-dependent protein kinase (cGK) is one of the major pathways for the cGMP cascade and has been demonstrated to inhibit platelet aggregation, relax smooth muscle cells, and control cardiocyte contractility. There are two subtypes of the type I cGK, cGKIalpha and cGKIbeta. The former is more sensitive to cGMP than the latter. In humans, cGKIbeta cDNA was isolated, but the full structure and tissue-specific gene expression of cGKIalpha have not been determined. The significance of cGK in human cardiovascular diseases has not been investigated at the molecular level. In the present study, we isolated the full-length human CGKIalpha cDNA (-36 to +2177; the translation start site: +1) enclosing the 671-amino acid protein. Nucleotides +267 to +2177 of the isolated cDNA were identical to the corresponding nucleotides of human cGKIbeta cDNA. Southern blot analysis suggested that human cGKIalpha and cGKIbeta are generated by alternative splicing of a single gene assigned to chromosome 10. By Northern blot analysis, we detected abundant human cGKIalpha mRNA (7.0 kb) in the aorta, heart, kidneys, and adrenals. In contrast, human cGKIbeta mRNA (7.0 kb) was detected abundantly only in the uterus. In cultured vascular smooth muscle cells, the type I cGK mRNA concentration was reduced to 10% of the basal level by 4 x 10(-10) mol/L platelet-derived growth factor. Angiotensin II (10(-8) mol/L), transforming growth factor-beta (4 x 10(-11) mol/L), and tumor necrosis factor-alpha (6 x 10(-6) mol/L) also exhibited an inhibitory effect on type I cGK gene expression. These findings suggest a pathophysiological implication of the type I cGK in cardiovascular diseases, including hypertension and atherosclerosis.
Hypertension 1996 Mar
PMID:cDNA cloning and gene expression of human type Ialpha cGMP-dependent protein kinase. 861 2

Adrenomedullin has recently been isolated from human pheochromocytoma. We designed the present study to examine the effect of adrenomedullin on the production of the vasoconstrictive and growth-promoting peptide endothelin-1 (ET-1) after stimulation with platelet-derived growth factor (PDGF) in cultured rat glomerular mesangial cells. PDGF stimulated ET-1 production in a concentration-dependent manner. Rat adrenomedullin inhibited this stimulated ET-1 production in a concentration-dependent manner between 10(-7) and 10(-8) mol/L. Rat adrenomedullin also increased the cellular level of cAMP in a concentration-dependent manner between 10(-7) and 10(-8) mol/L. Human adrenomedullin was less effective than rat adrenomedullin with respect to inhibiting ET-1 production and increasing cAMP levels. The addition of 8-bromo-cAMP (10(-3) and 10(-4) mol/L) reduced PDGF-induced ET-1 production. Furthermore, forskolin (10(-4) and 10(-5) mol/L), an activator of adenylate cyclase, reduced PDGF-induced ET-1 production. In contrast, the basal production of ET-1 was not significantly altered by rat and human adrenomedullin. These results indicate that adrenomedullin inhibits PDGF-induced ET-1 production in cultured rat mesangial cells, probably through a cAMP-dependent process.
Hypertension 1996 Mar
PMID:Interaction of adrenomedullin and platelet-derived growth factor on rat mesangial cell production of endothelin. 861 21

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

Although angiotensin II (Ang II) and the heptapeptide Ang-(1-7) differ by only one amino acid, the two peptides produce different responses in vascular smooth muscle cells. We previously showed that Ang II stimulated phosphoinositide hydrolysis, whereas Ang II and Ang-(1-7) released prostaglandins. We now report that Ang II and Ang-(1-7) differentially modulate rat aortic vascular smooth muscle cell growth. Ang-(1-7) inhibited [3H]thymidine incorporation in response to stimulation by fetal bovine serum, platelet-derived growth factor, or Ang II. The reduction in serum-stimulated thymidine incorporation by Ang-(1-7) depended on the concentration of the heptapeptide over the range of 1 nmol/L to 1 mumol/L, with a maximal inhibition of 60% by 1 mumol/L Ang-(1-7). Ang-(1-7) also inhibited the serum-stimulated increase in cell number to a maximum of 77% by 1 mumol/L Ang-(1-7). The attenuation of serum-stimulated thymidine incorporation by Ang-(1-7) was unaffected by antagonists selective for angiotensin type 1 (AT1) or type 2 (AT2) receptors; however, [Sar1,Ile1]Ang II and [Sar1,Thr2]Ang II were effective antagonists, indicating that growth inhibition by Ang-(1-7) was a result of angiotensin receptor activation. In contrast, Ang II stimulated [3H]thymidine incorporation in cultured vascular smooth muscle cells over the same concentration range, with a maximal stimulation of 314% at 1 mumol/L Ang II. Ang II also increased the total number of cells (to 145% of control), suggesting that enhanced thymidine incorporation was associated with vascular smooth muscle cell proliferation. The AT1 antagonist losartan or L-158,809 but not AT2 antagonists blocked [3H]thymidine incorporation by Ang II. These results suggest that Ang-(1-7) and Ang II exhibit opposite effects on the regulation of vascular smooth muscle cell growth. The inhibition of proliferation by Ang-(1-7) appears to be mediated by a novel angiotensin receptor that is not inhibited by AT1 or AT2 receptor antagonists.
Hypertension 1996 Jul
PMID:Angiotensin-(1-7) inhibits vascular smooth muscle cell growth. 867 48

In IgA nephritis (IgA Nx) there is a general defect in clearance of immune complexes. IgA molecules are poorly solubilised by the complement system and allows its deposition in the kidney. In patients with IgA Nx there is a defect both in the sera and in the renal tissue. Lack of genetically mediated mesangial reactivity towards IgA Nx prevents clinical and histological manifestations of IgA Nx. Binding of IgA deposits to mesangial cells causes secretion of cytokines associated with a decrease in prostaglandin E2 synthesis and increases in thromboxane A2 production which promotes mesangial cell proliferation. Angiotensin II induces mesangial cell contraction and efferent arteriovasoconstriction. Any form of therapy for IgA Nx must be rational and practical. To limit amounts of mesangial deposits one may attempt to reduce antigen load, down-regulate lymphokines and employ enzymes to remove glomerular immune deposits. The Department's guidelines for therapy of IgA Nx consist of control of systemic hypertension, use of angiotensin II converting enzyme inhibitor for glomerular hyperfiltration, dipyridamole and low-dose warfarin, a low protein diet and control of serum cholesterol to prevent lipid-induced glomerulosclerosis. Future therapeutic strategies may include inhibition of mediators and cytokines (platelet-derived growth factor antagonists and tumour necrosis factor inhibitors) and gene therapy.
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PMID:Recent concepts in the pathogenesis and therapy of IgA nephritis. 879 19

In addition to its vasoconstrictor and aldosterone-stimulating action, angiotensin II also drives cell growth and replication in the cardiovascular system, which may result in myocardial hypertrophy and hypertrophy or hyperplasia of conduit and resistance vessels in certain subjects. These actions are mediated through angiotensin II receptors (subtype AT1), which activate the G protein, phospholipase C, diacylglycerol and inositol trisphosphate pathway, to increase the expression of certain protooncogenes (c-fos, c-myc and c-jun) and growth factors (platelet-derived growth factor-A-chain, transforming growth factor-beta 1 and basic fibroblast growth factor). The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia). In genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia or remodeling, whereas in renovascular hypertension there is hypertrophy of vascular smooth muscle cells. Angiotensin II also increases synthesis of some matrix components, activates blood monocytes and is thrombogenic. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension; this seems to be a class effect, shared to some extent with calcium channel blocking agents. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries in hypertension and increase arterial compliance. These properties are also shared by losartan, the first of the new class of angiotensin II receptor (AT1) antagonists. The clinical implications of these findings need to be tested through rigorous and prospective clinical trials.
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PMID:The renin-angiotensin system and vascular hypertrophy. 883 52

Pericytes, also known as Rouget cells or mural cells, are associated abluminally with all vascular capillaries and post-capillary venules. Differences in pericyte morphology and distribution among vascular beds suggest tissue-specific functions. Based on their location and their complement of muscle cytoskeletal proteins, pericytes have been proposed to play a role in the regulation of blood flow. In vitro studies demonstrating the contractile ability of pericytes support this concept. Pericytes have also been suggested to be oligopotential and have been reported to differentiate into adipocytes, osteoblasts and phagocytes. The mechanisms involved in vessel formation have yet to be elucidated but observations indicate that the primordial endothelium can recruit undifferentiated mesenchymal cells and direct their differentiation into pericytes in microvessels, and smooth muscle cells in large vessels. Communication between endothelial cells and pericytes, or their precursors, may take many forms. Soluble factors such as platelet-derived growth factor and transforming growth factors-beta are likely to be involved. In addition, physical contact mediated by cell adhesion molecules, integrins and gap junctions appear to contribute to the control of vascular growth and function. Development of culture methods has allowed some functions of pericytes to be directly examined. Co-culture of pericytes with endothelial cells leads to the activation of transforming growth factor-beta, which in turn influences the growth and differentiation of the vascular cells. Finally, the pericyte has been implicated in the development of a variety of pathologies including hypertension, multiple sclerosis, diabetic microangiopathy and tumor vascularization.
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PMID:Pericytes in the microvasculature. 891 87

In the present study, we describe possible mechanisms by which hypercholesterolemia may contribute to the development of cardiovascular diseases. Treatment of rat aortic smooth muscle cells for 20 hours with cholesterol-rich liposomes (500 micrograms/mL cholesterol, 100 micrograms/mL low-density lipoprotein) resulted in a 76 +/- 12% increase in total cholesterol content. The effects of cholesterol enrichment were examined by determination of changes in cell membrane fluidity. Fluidity of the cholesterol-enriched cell membranes was decreased at all temperatures between 15 degrees C and 40 degrees C. Changes in membrane fluidity in whole cell membranes represented changes in fluidity of microsomal membranes isolated by Percoll gradient ultracentrifugation. The basal [Ca2+]i and the maximal platelet-derived growth factor (PDGF)-BB-induced [Ca2+]i was elevated by 30% and 90% in cholesterol-enriched cells, respectively. In contrast, the resting pH, and the PDGF-BB-induced stimulation of the Na+/H+ exchange were not affected in cholesterol-enriched cells. The effect of PDGF-BB on [3H]thymidine incorporation in cholesterol-enriched cells was elevated by 40% in comparison with untreated cells. Our findings show that cellular cholesterol may be involved in the development of vascular diseases via modulation of the PDGF-induced increase in [Ca2+]i and DNA synthesis in vascular smooth muscle cells.
Hypertension 1997 Jan
PMID:Cholesterol enhances platelet-derived growth factor-BB-induced [Ca2+]i and DNA synthesis in rat aortic smooth muscle cells. 903 23

Exposure of rat aortic vascular smooth muscle cells to alpha-thrombin resulted in the appearance of sis-inducing factor-A (SIF-A)-like DNA binding activity. This response to alpha-thrombin was delayed (detectable at 1 hour) compared with the rapid activation (15 to 30 minutes) by platelet-derived growth factor and the cytokine interleukin-6. alpha-Thrombin-induced SIF-A was sensitive to treatment with the tyrosine kinase inhibitor genistein. The thrombin inhibitor hirudin prevented the alpha-thrombin-mediated SIF-A induction. Cycloheximide had no effect on the ability of alpha-thrombin to induce SIF-A, suggesting that induction does not require new protein synthesis. alpha-Thrombin-induced SIF-A could be resolved into two additional subcomplexes termed SIF-A, and SIF-As. Antibodies against Stat3 reacted with alpha-thrombin-induced SIF-Af, suggesting that Stat3 or a related protein is present in this subcomplex. Induction of SIF-A DNA binding activity may contribute to alpha-thrombin-mediated cellular responses, including wound healing, cell proliferation, and inflammation in the vasculature.
Hypertension 1997 Jan
PMID:Alpha-thrombin stimulates sis-inducing factor-A DNA binding activity in rat aortic smooth muscle cells. 903 27

Vascular smooth muscle cell (VSMC) hypertrophy is believed to play some roles in atherosclerosis. To elucidate the role of vascular D1-like receptors in VSMC hypertrophy, the effects of dopamine and specific D1-like receptor agonists SKF 38393 and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC hypertrophy was studied. We observed that cells stimulated by PDGF-BB 5 ng/mL showed increased VSMC hypertrophy. These effects were prevented by coincubation with dopamine, SKF 38393, and YM 435 1-10 mumol/L, and this prevention was reversed by Sch 23390 1 to 10 mumol/L, a specific D1-like receptor antagonist. These actions are mimicked by forskolin 1 to 10 mumol/L, a direct activator of adenylate cyclase and 8-bromo-cAMP 0.1 to 1 mmol/L, and are blocked by a specific protein kinase A (PKA) inhibitor N-[2-(P-bromcoinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H89) but not blocked by its negative control. PDGF-BB (5 ng/mL)-mediated mitogen-activated protein kinase (MAPK) activity was significantly suppressed by coincubation with D1-like receptor agonists, which were reversed by PKA inhibitor H 89. These results suggest that vascular D1-like receptor agonists inhibit hypertrophy of VSMC, possibly through PKA activation and suppression of activated MAPK activity.
Hypertension 1997 Jan
PMID:Dopamine D1-like receptor stimulation inhibits hypertrophy induced by platelet-derived growth factor in cultured rat renal vascular smooth muscle cells. 903 26


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