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)

We investigated the effect of long-term in vivo blockade of the ET-1 receptor subtype B (ET(B)) with A-192621, a selective ET(B) antagonist, on atrial and ventricular natriuretic peptide (NP) gene expression in deoxycorticosterone acetate (DOCA)-salt hypertension. In this model, stimulation of the cardiac natriuretic peptide (NP) and the endothelin system and suppression of the renin-angiotensin system is observed. DOCA-salt induced significant hypertension, cardiac hypertrophy and increased NP plasma and left atrial and right and left ventricular NP gene expression. ET(B) blockade per se produced hypertension and left ventricular hypertrophy but induced little change on the levels of ventricular NP and only increased left atrial natriuretic factor (ANF) mRNA levels. Combined ET(B) blockade/DOCA-salt treatment worsened hypertension, increased left ventricular hypertrophy and induced right ventricular hypertrophy. All animals so treated had increased ventricular NP gene expression. Collagen III and beta-myosin heavy chain gene expression were enhanced in both the right and the left ventricle of DOCA-salt hypertensive rats. The results of this study suggest that the ET(B) receptor does not participate directly in the modulation of atrial or ventricular NP gene expression and that this receptor mediates a protective cardiovascular function. ET(B) blockade can induce significant ventricular hypertrophy without an increase in ANF or brain NP gene expression.
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PMID:Natriuretic peptide gene expression in DOCA-salt hypertension after blockade of type B endothelin receptor. 1183 12

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

Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Atrial natriuretic peptide (ANP) has been postulated to exert local antihypertrophic effects in the heart. Thus, a loss of function of the ANP receptor guanylyl cyclase-A (GC-A) might contribute to the increased propensity to cardiac hypertrophy, although a causative role in vivo has not been definitively demonstrated. To test whether local ANP modulates cardiomyocyte growth, we inactivated the GC-A gene selectively in cardiomyocytes by homologous loxP/Cre-mediated recombination. Thereby we have circumvented the systemic, hypertensive phenotype associated with germline inactivation of GC-A. Mice with cardiomyocyte-restricted GC-A deletion exhibited mild cardiac hypertrophy, markedly increased mRNA expression of cardiac hypertrophy markers such as ANP (fivefold), alpha-skeletal actin (1.7-fold), and beta-myosin heavy chain (twofold), and increased systemic circulating ANP levels. Their blood pressure was 7-10 mmHg below normal, probably because of the elevated systemic levels and endocrine actions of ANP. Furthermore, cardiac hypertrophic responses to aortic constriction were enhanced and accompanied by marked deterioration of cardiac function. This phenotype is consistent with a local function of the ANP/GC-A system to moderate the molecular program of cardiac hypertrophy.
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PMID:Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. 1272 15

Caveolae are omega-shaped organelles of the cell surface. The protein caveolin-3, a structural component of cardiac caveolae, is associated with cellular signaling. To investigate the effect of adenovirus-mediated overexpression of caveolin-3 on hypertrophic responses in cardiomyocytes, we constructed an adenovirus that encoded human wild-type caveolin-3 (Ad.Cav-3), mutant caveolin-3 (Ad.Cav-3Delta), or bacterial beta-galactosidase (Ad.LacZ). This mutant has been reported to cause human limb-girdle muscular dystrophy. It lacks 9 nucleotides in the caveolin scaffolding domain and behaves in a dominant-negative fashion. Rat neonatal cardiomyocytes were infected with the virus and then harvested 36 hours after infection. In noninfected cells, phenylephrine (PE) and endothelin-1 (ET) increased cell size and [3H]leucine incorporation, along with the induction of sarcomeric reorganization and the reexpression of beta-myosin heavy chain, indicating myocyte hypertrophy. Infection with Ad.LacZ had no effect on those parameters. Ad.Cav-3 prevented the PE- and ET-induced increases in cell size, leucine incorporation, sarcomeric reorganization, and reexpression of beta-myosin heavy chain. Ad.Cav-3 also blocked the PE- and ET-induced phosphorylations of extracellular signal-regulated kinases (ERKs) but did not affect c-Jun amino-terminal kinase and p38 mitogen-activated protein kinase activities. In contrast, Ad.Cav-3Delta significantly augmented hypertrophic responses to ET, which were associated with increased ET-induced phosphorylation of ERK1/2. These results suggest that caveolin-3 behaves as a negative regulator of hypertrophic responses, probably through suppression of ERK1/2 activity.
Hypertension 2003 Aug
PMID:Adenovirus-mediated overexpression of caveolin-3 inhibits rat cardiomyocyte hypertrophy. 1284 14

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease, which may afflict as many as 1 in 500 subjects (0.2%), being probably the most common hereditary cardiovascular disease and the most common cause of sudden cardiac death (SCD). Hypertrophic cardiomyopathy is characterized by the presence of unexplained left ventricular hypertrophy (in absence of hypertension, valvular disease, etc), which is usually asymmetric and involves the ventricular septum. Molecular genetic studies have identified eleven genes that code proteins of the sarcomere that are associated with the HCM; the beta-myosin heavy chain gene (MYH7), alpha-myosin heavy chain (MYH6), cardiac troponin T (TNNT2); cardiac troponin C (TNNC1), alpha-tropomyosin (TPM1), myosin binding protein-C (MYBPC3), cardiac troponin (TNNI3), essential and regulatory light chain genes (MYL3 and MYL2, respectively), cardiac alpha-actin gene (ACTC) and titin (TTN). The objective of this paper is the revision of the current state of the knowledge on (1) the organization and mutations of the HCM causing genes and their proteins and (2) the animal models developed for the study of the genes, mutations and proteins in the hypertrophic cardiomyopathy.
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PMID:[Familial hypertrophic cardiomyopathy: genes, mutations and animal models. A review]. 1505 60

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of AhR results in hypertension, and cardiac hypertrophy and fibrosis, associated with elevated plasma angiotensin II (Ang II) and endothelin-1 (ET-1), thus AhR appears to contribute to cardiovascular homeostasis. In these studies, we tested the hypothesis that ET-1 mediates cardiovascular pathology in AhR null mice via ETA receptor activation. First, we determine the time courses of cardiac hypertrophy, and of plasma and tissue ET-1 expression in AhR wildtype and null mice. AhR null mice exhibited increases in heart-to-body weight ratio and age-related expression of cardiac hypertrophy markers, beta-myosin heavy chain (beta-MHC), and atrial natriuretic factor (ANF), which were significant at 2 months. Similarly, plasma and tissue ET-1 expression was significantly elevated at 2 months and increased further with age. Second, AhR null mice were treated with ETA receptor antagonist, BQ-123 (100 nmol/kg/day), for 7, 28, or 58 days and blood pressure, cardiac fibrosis, and cardiac hypertrophy assessed, respectively. BQ-123 for 7 days significantly reduced mean arterial pressure in conscious, catheterized mice. BQ-123 for 28 days significantly reduced the histological appearance of cardiac fibrosis. Treatment for 58 days significantly reduced cardiac mass, assessed by heart weight, echocardiography, and beta-MHC and ANF expression; and reduced cardiac fibrosis as determined by osteopontin and collagen I mRNA expression. These findings establish ET-1 and the ETA receptor as primary determinants of hypertension and cardiac pathology in AhR null mice.
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PMID:Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice. 1609 89

We tested the hypothesis that the renin inhibitor aliskiren ameliorates organ damage in rats transgenic for human renin and angiotensinogen genes (double transgenic rat [dTGR]). Six-week-old dTGR were matched by albuminuria (2 mg per day) and divided into 5 groups. Untreated dTGR were compared with aliskiren (3 and 0.3 mg/kg per day)-treated and valsartan (Val; 10 and 1 mg/kg per day)-treated rats. Treatment was from week 6 through week 9. At week 6, all groups had elevated systolic blood pressure (BP). Untreated dTGR showed increased BP (202+/-4 mm Hg), serum creatinine, and albuminuria (34+/-5.7 mg per day) at week 7. At week 9, both doses of aliskiren lowered BP (115+/-6 and 139+/-5 mm Hg) and albuminuria (0.4+/-0.1 and 1.6+/-0.6 mg per day) and normalized serum creatinine. Although high-dose Val lowered BP (148+/-4 mm Hg) and albuminuria (2.1+/-0.7 mg per day), low-dose Val reduced BP (182+/-3 mm Hg) and albuminuria (24+/-3.8 mg per day) to a lesser extent. Mortality was 100% in untreated dTGR and 26% in Val (1 mg/kg per day) treated rats, whereas in all other groups, survival was 100%. dTGR treated with low-dose Val had cardiac hypertrophy (4.4+/-0.1 mg/g), increased left ventricular (LV) wall thickness, and diastolic dysfunction. LV atrial natriuretic peptide and beta-myosin heavy chain mRNA, albuminuria, fibrosis, and cell infiltration were also increased. In contrast, both aliskiren doses and the high-dose Val lowered BP to a similar extent and more effectively than low-dose Val. We conclude that in dTGR, equieffective antihypertensive doses of Val or aliskiren attenuated end-organ damage. Thus, renin inhibition compares favorably to angiotensin receptor blockade in reversing organ damage in dTGR.
Hypertension 2005 Sep
PMID:Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. 1610 63

We investigated whether or not p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. We used double transgenic rats harboring both human renin and angiotensinogen genes (dTGRs). dTGR, with or without p38 inhibitor (BIRB796; 30 mg/kg per day in the diet), and nontransgenic Sprague-Dawley rats were studied in 2 protocols. In protocol 1 (week 7), systolic blood pressure of untreated dTGRs was 204+/-4 mm Hg, but partially reduced after BIRB796 treatment (166+/-7 mm Hg), whereas Sprague-Dawley rats were normotensive. The cardiac hypertrophy index was unchanged in untreated and BIRB796-treated dTGRs. The beta-myosin heavy chain expression of BIRB796-treated hearts was significantly lower in BIRB796 compared with dTGRs, indicating a delayed switch to the fetal isoform. BIRB796 treatment significantly reduced cardiac fibrosis, connective tissue growth factor, tumor necrosis factor-alpha, interleukin-6, and macrophage infiltration. Albuminuria was not reduced in BIRB796-treated dTGRs. Tubular and glomerular damage with tumor necrosis factor-alpha expression was unaltered, although serum creatinine and cystatin C were normalized. Renal macrophage infiltration, fibrosis, and vessel damage were reduced. In protocol 2 (week 8), we focused on mortality and arrhythmogenic electrical remodeling. Mortality of untreated dTGRs was 100% but was reduced to 10% in the BIRB796 group. Cardiac magnetic field mapping showed prolongation of depolarization and repolarization in untreated dTGRs compared with Sprague-Dawley rats with a partial reduction by BIRB796. Programmed electrical stimulation elicited ventricular tachycardias in 81% of untreated dTGRs but only in 48% of BIRB796-treated dTGRs. In conclusion, BIRB796 improved survival, target organ damage, and arrhythmogenic potential in angiotensin II-induced target organ damage.
Hypertension 2007 Mar
PMID:p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. 1722 70

Collagen accumulates disproportionately in cardiac remodeling induced by hypertension and associated with advancing age. Spironolactone (Spiro), an aldosterone antagonist, attenuates the accumulation of collagen induced by hypertension. It was hypothesized that Spiro would attenuate the age-associated increase in percent collagen in the heart. Female Fisher 344 rats at 3 months (Y), 12 months (M), and 21 months (O) of age were treated with Spiro (30 mg/kg/d) or vehicle (Veh) for 2 months, yielding six groups: Y-Veh, Y-Spiro, M-Veh, M-Spiro, O-Veh, and O-Spiro. Hearts were harvested for immunoblotting, RNA blotting, and biochemical analysis. Percent collagen in the left ventricle and septum was greatest in the oldest rats. Spiro did not significantly attenuate the age-associated increase in collagen fraction or the age-associated increases in expression of atrial natriuretic factor and beta-myosin heavy chain messenger RNA. Chronic aldosterone antagonism does not attenuate the age-associated increase in collagen fraction in the female Fisher 344 rat heart.
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PMID:Aldosterone antagonism fails to attenuate age-associated left ventricular fibrosis. 1745 31

Cardiac remodeling is a key event in both diabetic and hypertensive heart diseases. In the present study, we investigated early myocardial changes in an animal model, the male Sabra rat model (SBH/y) of salt-induced hypertension-rendered diabetic with streptozotocin. Control non-diabetic (C), diabetic (D), and D or C rats made hypertensive by salt loading (DS or CS) were studied after 6 weeks. M-mode echocardiography revealed that left ventricular internal dimension during diastole and systole were significantly increased in D and DS, but not in C or CS. Concurrently, we found in D and DS an increase in cardiac beta-myosin heavy chain, atrial natriuretic peptide, skeletal alpha-actin mRNA, type III collagen, and transforming growth factor-beta. Myocardial angiotensin-converting enzyme (ACE) mRNA levels were increased while ACE2 mRNA levels were decreased in both D and DS groups. Cardiac angiotensin-1 (AT1) receptor protein levels were unchanged but the levels of phosphorylated (p) ERK and Jun-NH(2)-protein kinase (JNK) were increased in D and DS. In conclusion, we detected early cardiac changes in diabetic rats that were unrelated to hypertension. The increase in ACE, the decrease in ACE2, and the increase in cardiac pERK and pJNK suggest an increase in free angiotensin II and AT1R signaling in the diabetic myocardium as a possible mechanism contributing to cardiac remodeling in diabetes.
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PMID:Early blood pressure-independent cardiac changes in diabetic rats. 1837 34


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