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 this study, we used the somatic gene delivery approach to explore the role of the kallikrein-kinin system (KKS) in cardiac remodeling and apoptosis after myocardial infarction (MI). Rats were subjected to coronary artery ligation to induce MI, and adenovirus carrying the human tissue kallikrein or luciferase gene was injected into the tail vein at 1 week after surgery. Cardiac output gradually decreased from 2 to 6 weeks after MI, whereas delivery of the kallikrein gene prevented this decrease. Cardiac responses to dobutamine-induced stress were improved in rats receiving kallikrein gene as compared with rats receiving control virus at 6 weeks after MI. Kallikrein significantly improved cardiac remodeling by decreasing collagen density, cardiomyocyte size, and left ventricular internal perimeter and increasing capillary density in the heart at 6 weeks after MI. Kallikrein gene transfer attenuated myocardial apoptosis, which was positively correlated with remodeling parameters in the heart at 2 weeks after MI. Endothelial dysfunction, characterized by increased vascular resistance, decreased left ventricular blood flow, and decreased cardiac nitric oxide levels, existed in remodeled hearts at 2 weeks after MI, whereas kallikrein gene transfer improved these parameters. Kallikrein gene delivery improved cell survival parameters as shown by increased phospho-Akt and reduced caspase-3 activation at 2 weeks after MI. This study indicates that the kallikrein-kinin system plays an important role in preventing the progression of heart failure by attenuating cardiac hypertrophy and fibrosis, improving endothelial function, and inhibiting myocardial apoptosis through the Akt-mediated signaling pathway.
Hypertension 2002 Nov
PMID:Kallikrein gene delivery improves cardiac reserve and attenuates remodeling after myocardial infarction. 1241 58

Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms in response to a chronic blood pressure increase. Vasoactive peptides, such as endothelin, participate in hypertension-associated vascular fibrosis by stimulating collagen I formation and increasing contractility of arterial wall. In the present study, we tested the hypothesis that activation of the epidermal growth factor (EGF) receptor pathway mediates these events. Experiments were performed in transgenic mice harboring the luciferase gene under the control of the collagen I-alpha2 chain promoter. Endothelin induced a rapid phosphorylation of the mitogen-activated protein kinase (MAPK)/ERK and increased collagen I gene activity in freshly isolated aortas. This effect of endothelin was totally inhibited by an endothelin receptor antagonist, an EGF receptor phosphorylation inhibitor, and a blocker of the MAPK/ERK cascade. In parallel experiments, inhibition of EGF receptor phosphorylation decreased the endothelin-induced pressor effect in isolated aortic rings and in anesthetized animals in vivo. In addition, the endothelin-induced increase of blood pressure was blunted in the waved-2 mice, a strain expressing functionally impaired EGF receptors. Our results provide the first evidence that the EGF receptor mediates at least two of the major actions of endothelin in the vascular tissue: contractility and fibrogenesis.
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PMID:Epidermal growth factor receptor trans-activation mediates the tonic and fibrogenic effects of endothelin in the aortic wall of transgenic mice. 1247 99

The activity of the atrial natriuretic peptide receptor (Npr1) is altered in spontaneously hypertensive rats (SHR) in relation to its mRNA levels, suggesting abnormal transcriptional control in hypertension. A single-stranded conformational polymorphism caused by a repetitive dinucleotide segment of 10 TA in BN-Lx and of 40 TA in SHR was localized at position -943 relative to the transcription start site of the Npr1 gene, downstream of a putative cGMP-regulatory region, and was the only sequence difference noted between the two strains. Transient transfections of -1520 to -920 Npr1 promoter-SV40-luciferase fusion vector showed that the construct from BN-Lx stimulated the SV40 promoter, whereas that from SHR slightly inhibited it. In contrast to the BN-Lx construct, the activity of the SHR fragment was refractory to downregulation by atrial natriuretic peptide. Genotype-phenotype correlation studies in recombinant inbred strains (RIS) derived from BN-Lx and SHR crosses revealed significant correlations of the TA repeat with basal guanylyl cyclase activity and Npr1 mRNA levels. The correlations were heightened by a locus on chromosome 10 containing the Ace gene. The highest basal guanylyl cyclase activity and Npr1 mRNA values were found in RIS with both genes (Npr1/Ace) of BN genotypes, whereas the lowest were recorded in RIS, with the SHR genotypes at both loci. This was inversely correlated with diastolic blood pressure in these strains. In conclusion, the longer TA repeat unit in the promoter of Npr1 of SHR, in tandem with a putative cGMP responsive element, regulates the transcription of the Npr1 gene with consequences on diastolic blood pressure.
Hypertension 2003 Jan
PMID:TA repeat variation, Npr1 expression, and blood pressure: impact of the Ace locus. 1251 24

Thyroid hormone has a broad effect on cardiovascular system. 3,3',5-triiodo-l-thyronine (T3), a biologically active form of thyroid hormone, increases cardiac contractility. T3 causes arterial relaxation and reduction of systemic vascular resistance, resulting in an increase in cardiac output. However, the molecular mechanisms of vascular relaxation by T3 are incompletely characterized. We studied the effect of T3 on the angiotensin (Ang) II type 1 receptor (AT1R) expression in vascular smooth muscle cells. T3 dose-dependently decreased expression levels of AT1R mRNA, with a peak at 6 hours of stimulation. Binding assay using [125I]Sar1-Ile8-Ang II revealed that AT1R number was decreased by stimulation with T3 without changing the affinity to Ang II. T3 reduced calcium response of vascular smooth muscle cells to Ang II by 26%. AT1R promoter activity measured by luciferase assay was reduced by 50% after 9 hours of T3 administration. mRNA stability was also decreased by T3. Real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis revealed that AT1R mRNA and protein were downregulated in the aorta of T3-treated rats. These results suggest that T3 downregulates AT1R expression both at transcriptional and posttranscriptional levels, and attenuates biological function of Ang II. Our results suggest that downregulation of AT1R gene expression may play an important role for T3-induced vascular relaxation.
Hypertension 2003 Mar
PMID:Downregulation of vascular angiotensin II type 1 receptor by thyroid hormone. 1262 65

Hypoxia causes several renal tubular dysfunctions, including abnormal handling of potassium and sodium and increased blood pressure. Therefore, we investigated the impact of hypoxia on 11beta-hydroxysteroid dehydrogenase (11beta-HSD2) enzyme, a crucial prereceptor gatekeeper for renal glucocorticosteroid-mediated mineralocorticoid action. The effect of hypoxia was assessed in vitro by incubating LLC-PK1 cells with antimycin A, an inhibitor of mitochondrial oxidative phosphorylation. Antimycin A induced a dose- and time-dependent reduction of 11beta-HSD2 activity. The early growth response gene, Egr-1, a gene known to be stimulated by hypoxia was investigated because of a potential Egr-1 binding site in the promoter region of 11beta-HSD2. Antimycin A induced Egr-1 protein and Egr-1-regulated luciferase gene expression. This induction was prevented with the MAPKK inhibitor PD 98059. Overexpression of Egr-1 reduced endogenous 11beta-HSD2 activity in LLC-PK1 cells, indicating that MAPK ERK is involved in the regulation of 11beta-HSD2 in vitro. In vivo experiments in rats revealed that Egr-1 protein increases, whereas 11beta-HSD2 mRNA decreases, in kidney tissue after unilateral renal ischemia and in humans the renal activity of 11beta-HSD2 as assessed by the urinary ratio of (tetrahydrocortisol+5alpha-tetrahydrocortisol)/tetrahydrocortisone declined when volunteers were exposed to hypoxemia at high altitude up to 7000 m. Thus, hypoxia decreases 11beta-HSD2 transcription and activity by inducing Egr-1 in vivo and in vitro. This mechanism might account for enhanced renal sodium retention and hypertension associated with hypoxic conditions.
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PMID:Hypoxia causes down-regulation of 11 beta-hydroxysteroid dehydrogenase type 2 by induction of Egr-1. 1262 38

Ras-related GTPase (Ral) is converted to the GTP-bound form by Ral GDP dissociation stimulator (Ral-GDS), a putative effector protein of Ras. Although a number of studies indicate that Ras induces cardiac hypertrophy, the functional role of Ral-GDS/Ral signaling pathway is as yet unknown in cardiac myocytes. We investigated the role of the Ral-GDS/Ral pathway in cardiac hypertrophy. Transfection of Ral-GDS and constitutively active mutant of Ral (RalG23V) in cultured rat neonatal myocytes stimulated promoter activity of c-fos (5.4-fold and 2.6-fold, P<0.01), alpha-skeletal actin (2.7-fold and 2.1-fold, P<0.01), and beta-myosin heavy chain-luciferase (2.8-fold and 2.3-fold, P<0.01). Ral-GDS-induced or RalG23V-induced promoter activation was increased synergistically with activated Ras (RasG12V). Dominant-negative mutant of Ral (RalS28N) partially inhibited RasG12V induced promoter activation. Cardiac myocytes transfected with RalG23V showed increased cell size compared with nontransfected or vector-transfected cells (2.1-fold, P<0.01). Cardiotrophin-1 (CT-1) upregulated Ral-GDS mRNA expression and induced Ral activation. CT-1-induced Ral-GDS mRNA expression was inhibited by overexpression of the dominant-negative mutant of STAT3. Moreover, Ral activity was elevated in hypertrophied hearts (2.1-fold, P<0.01) by mechanical stress in association with increased CT-1 expression and signal transducer and activator of transcription 3 (STAT3) phosphorylation in the rat aortic banding model. Ral-GDS/Ral pathway is involved in a wide range of gene expressions and is activated by hypertrophic stimuli in vitro and in vivo. SATA3 may play a key role in Ral-GDS expression and Ral activation. Our data provide evidence that the Ral-GDS/Ral signaling pathway is a link to the process of cardiac hypertrophy.
Hypertension 2003 Apr
PMID:Ral GDP dissociation stimulator and Ral GTPase are involved in myocardial hypertrophy. 1264 11

Apoptosis of cardiac myocytes is thought to be a feature of many pathological disorders, including congestive heart failure (CHF) and ischemic heart disease (IHD). Because recent investigations indicate that endothelin-1 (ET-1) plays an important role in CHF and IHD, we investigated the effect of ET-1 on cardiomyocyte apoptosis. The presence of apoptosis in rat cardiomyocytes (H9c2 and neonatal) was evaluated by morphological criteria, electrophoresis of DNA fragments, 4',6'-diamidine-2'-phenylindole staining, and TUNEL analysis. ET-1, but not angiotensin II, prevented apoptosis induced by serum deprivation via ETA receptors in a dose-dependent manner (1 to 100 nmol/L). ET-1 also prevented cytochrome c release from mitochondria to the cytosol. The use of specific pharmacological inhibitors demonstrated that the antiapoptotic effect of ET-1 was mediated through a tyrosine kinase pathway (genistein and AG490) but not through protein kinase C (PKC; calphostin C), mitogen-activated protein kinases (PD98059 and SB203580), or PKA (KT5270) pathways. Adenovirus-mediated gene transfer of kinase-inactive (KI) c-Src reversed the antiapoptotic effect of ET-1. We further investigated whether Bcl-xL, an antiapoptotic molecule, would be upregulated by using a luciferase-based reporter system. ET-1 upregulated Bcl-xL, and this upregulation was inhibited by genistein or AG490 but not by calphostin C. The experiments with KI mutants for various tyrosine kinases revealed that c-Src and Pyk2 (but not JAK1, Jak2, Syk, and Tec) are involved in ET-1-induced upregulation of Bcl-xL expression. These findings suggest that ET-1 prevents apoptosis in cardiac myocytes through the ETA receptor and the subsequent c-Src/Bcl-xL-dependent pathway.
Hypertension 2003 May
PMID:Antiapoptotic effect of endothelin-1 in rat cardiomyocytes in vitro. 1266 84

Hypertension is a complex trait with multiple genetic determinants. A previous genome-wide linkage study of systolic blood pressure in a mouse genetic backcross implicated a region of chromosome 13 (LOD = 3.3 at 16.0 cM) as a determinant of blood pressure differences between a hereditary low blood pressure strain of Mus musculus (BPL/1) and Mus spretus (SPRET); at this locus, the unexpected effect of the BPL/1 allele was to increase blood pressure. A plausible candidate locus encoding angiotensin II receptor isoform 1a (Agtr1a) is also located at 16.0 cM on chromosome 13. We therefore investigated structural and functional differences at Agtr1a between BPL/1 and SPRET, as well as the BPH/2 strain. Resequencing Agtr1a in the three strains established the exon/intron and proximal promoter structure of the mouse gene. Coding exon 3 spanned 1,960 bp (with 26 SNPs), including the 1,077-bp/359-amino acid ORF (with 5 cSNPs, all of which were synonymous). Promoter sequences revealed a consensus TATA box, conserved G/C-rich regions, and a striking, lengthy simple sequence repeat region, composed of di-, tri-, tetra-, and penta-nucleotide repeats, whose overall length varied markedly among the strains. Twenty-five other SNPs and three single nucleotide deletions differentiated the strains' promoters, six of which were in likely functional promoter motifs. Agtr1a mRNA abundance in the adrenal gland in vivo was greater (P < 0.05) in BPL/1 than SPRET, consistent with the predicted effect of the BPL/1 allele to confer higher blood pressure. When Agtr1a promoters were subcloned into luciferase reporter plasmids and transfected into PC12 chromaffin cells, basal promoter expression was higher (P < 0.001) in BPL/1 than in SPRET, consistent with the endogenous mRNA results. In summary, Agtr1a on chromosome 13 is highly polymorphic between mouse strains, although the amino acid sequence specified by the ORF is invariant, even across mouse species. We conclude that polymorphisms in the Agtr1a promoter account for differences in gene expression in vivo between BPL/1 and SPRET, in a way consistent with the effects of alleles at this locus on chromosome 13 to affect blood pressure in the mouse genome-wide linkage study.
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PMID:The angiotensin II receptor (Agtr1a): functional regulatory polymorphisms in a locus genetically linked to blood pressure variation in the mouse. 1269 7

Both integrin-based focal adhesion complexes and receptor tyrosine kinases have been proposed as scaffolds on which the G protein-coupled receptor (GPCR)-induced signaling complex might assemble. We have recently reported that Ca2+-sensitive tyrosine kinase, Pyk2, and epidermal growth factor receptor (EGFR) act as independently regulated scaffolds in cardiomyocytes. In this report, we investigated the activation and regulation of p130Cas, Crk, Pyk2, and c-Src by a well-known hypertrophic agonist, endothelin-1 (ET), and determined their contributions to the activation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in cardiomyocytes. Like Pyk2, ET-induced tyrosine phosphorylation of p130Cas was significantly inhibited by either chelating intracellular Ca2+ ([Ca2+]i) or a protein kinase C inhibitor, calphostin C. This activation of p130Cas was also abrogated by the tetrapeptide RGDS, which disrupts integrin heterodimerization; cytochalasin D, which depolymerizes the actin cytoskeleton; or a selective Src family kinase inhibitor, PP2, but not by an EGFR inhibitor, AG1478. We also observed ET-induced temporal associations of Pyk2 with active c-Src, followed by p130Cas with Pyk2, c-Src, and Crk. Overexpression of a dominant-negative mutant of p130Cas (CasDeltaSD), Crk (CrkSH2m), Pyk2 (PKM), or C-terminal Src kinase (Csk), but not of a deletion mutant of EGFR (533delEGFR), attenuated ET-induced JNK activation. Similarly, an ET-induced increase in c-jun promoter luciferase activity was inhibited by overexpression of CasDeltaSD, CrkSH2m, PKM, or Csk. In contrast, ET-induced ERK activation and c-fos gene expression were predominantly regulated by EGFR. Collectively, the focal adhesion-dependent p130Cas/Crk/Pyk2/c-Src-mediated pathway is selectively involved in ET-induced JNK activation in cardiomyocytes.
Hypertension 2003 Jun
PMID:Selective involvement of p130Cas/Crk/Pyk2/c-Src in endothelin-1-induced JNK activation. 1271 47

The hypothesis that cross-talk between membrane-active beta-adrenergic agonists and estrogens includes beta-adrenergic modulation of estrogen receptor (ER)-regulated gene expression was investigated. Vascular smooth muscle-derived A7r5 cells were transfected with an ERalpha expression plasmid (pCR3.1-hERalpha), the estrogen response element (ERE)-linked reporter pERE-E1b-luciferase (ERE-Luc), and pCMV-beta-galactosidase using a lysine-conjugated adenovirus transfection method. Hormone or agonist treatment and harvest followed 6 hours and 24 hours later, respectively. Treatment with 17beta-estradiol (E(2), 1 nmol/L) significantly stimulated ERE-Luc activity. Isoproterenol (10-9 to 10-6 mol/L) treatment alone did not stimulate ERE-Luc activity. Cotreatment with both E(2) and isoproterenol resulted in complete inhibition of E(2)-stimulated ERE-Luc activity. This isoproterenol effect was prevented by the beta-adrenergic antagonist propanolol (10-6 mol/L). Adrenomedullin treatment in these cells (1-50 nmol/L) did not inhibit ER/ERE-Luc activity, whether in the presence or absence of E(2). Moreover, isoproterenol did not affect vitamin D-stimulated VDRE-Luc expression, indicating that the inhibitory effect of isoproterenol on E(2)-directed ERE-Luc expression is specific among nuclear transcription factor receptors. Moreover, in MCF-7 breast cancer cells, there was no effect of isoproterenol on ER/ERE-directed transcription in the absence or presence of E(2), demonstrating tissue specificity of this isoproterenol effect. These studies demonstrate cross-talk between the beta-adrenergic agonist isoproterenol and ER-directed reporter gene expression in A7r5 cells. Furthermore, this cross-talk is specific with respect to agonist, nuclear receptor species, and cell type. These observations may have important implications both for the use of beta-adrenergic agents to treat hypertension and for possible gender-related differences in cardiovascular regulation.
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PMID:Cross-talk between beta-adrenergic stimulation and estrogen receptors: isoproterenol inhibits 17beta-estradiol-induced gene transcription in A7r5 cells. 1288 32


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