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)

A 73-year-old Japanese woman was referred for examination of right flank pain and progressive hypertension. Abdominal CT incidentally detected a right adrenal mass 8 cm in size. The tumor exhibited isodensity by CT and contained high-intense lesion by T2-weighted MRI. Scintigraphy with (131) I-metaiodobenzylguanidine and (131) I-adosterol showed no abnormal uptake by whole body scan. Positron emission tomography scan with (18) F-2-fluoro-D-deoxyglucose demonstrated an exclusive uptake in the right adrenal mass. Adrenocortical hormone levels and catecholamine secretion were within normal range; however, the level of serum neuron-specific enolase (NSE) was found to be markedly high. After controlling systemic blood pressure with an alpha1-blocker, the right adrenal tumor was surgically removed, along with the right kidney and inferior vena cava which adhered to it. The tumor was pathologically proven to be leiomyosarcoma, which was immunohistochemically positive with alpha-smooth muscle actin and negative with CD57, S-100 and c-kit proteins. Notably, NSE protein was massively expressed in the resected tumor. After surgery blood pressure was controlled with regular medication and serum NSE levels have since normalized. The possibility of leiomyosarcoma should be kept in mind in adrenal incidentalomas with rapid growth and atypical radiological images. Our findings suggest that circulating NSE levels may be clinically useful for early detection of recurrence.
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PMID:A rare tumor in the adrenal region: neuron-specific enolase (NSE)-producing leiomyosarcoma in an elderly hypertensive patient. 1825 May 40

Shroom is a PDZ-domain protein involved in the regulation and maintenance of cytoskeletal architecture by binding to actin. Hypertrophy and altered actin organisation of pulmonary arterial smooth muscle cells (PASMC) is a hallmark of pulmonary arterial hypertension (PAH). The aim of the present study was to localise and characterise Shroom expression in the lung in experimental and idiopathic PAH (IPAH). Shroom expression and localisation in hypoxia-induced PAH in mice and IPAH in humans, in vivo, as well as in primary PASMC, in vitro, was assessed by quantitative RT-PCR, immunofluorescence, laser-assisted microdissection and immunohistochemistry. Shroom localised exclusively to PASMC (both bronchial and vascular) in mouse and human lungs. Both in vivo and in primary PASMC, in vitro, Shroom exhibited spatially similar expression with alpha-smooth muscle actin (alpha-SMA). Shroom expression was significantly reduced in the mouse model of PAH, in primary murine PASMC exposed to hypoxia, and in primary PASMC isolated from patients with IPAH. The ratio between Shroom and alpha-SMA RNA expression further confirmed Shroom downregulation in both mouse and human PASMC. In summary, Shroom localises exclusively to pulmonary smooth muscle cells. Shroom downregulation in pulmonary arterial hypertension suggests a link between Shroom expression and pulmonary arterial smooth muscle cell hypertrophy in pulmonary arterial hypertension.
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PMID:Shroom expression is attenuated in pulmonary arterial hypertension. 1855 Jun 13

There is accumulating evidence indicating the role of aldosterone in the pathogenesis of hypertension and renal injury. In this study, we investigated the role of the Rho-kinase dependent signaling pathway in aldosterone-induced myofibroblastic transdifferentiation and collagen gene expression in rat mesangial cells (RMCs). Stimulation with aldosterone (1 nmol/L) significantly increased phosphorylation of myosin phosphatase target subunit-1 (MYPT-1), a marker of Rho-kinase activity, with a peak at 20 min in RMCs. Pre-incubation with a selective mineralocorticoid receptor antagonist, eplerenone (10 micromol/L), or a specific Rho-kinase inhibitor, Y27632 (10 micromol/L), attenuated the aldosterone-induced increase in MYPT-1 phosphorylation. Aldosterone also induced hypertrophy in RMCs, accompanied by an increase in actin polymerization and expression of alpha-smooth muscle actin (alpha-SMA), a myofibroblastic transdifferentiation marker. Collagen type I, III and IV mRNA levels were also increased with aldosterone stimulation. Pre-treatment with eplerenone or Y27632 prevented the aldosterone-induced cell hypertrophy, actin polymerization, the increase in alpha-SMA expression and the increases of collagen type I, III, IV mRNA levels in RMCs. These results suggest that aldosterone-induced mesangial cell hypertrophy is associated with cell transformation, leading to an increase in collagen gene expression via the Rho-kinase dependent signaling pathway.
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PMID:Aldosterone induces myofibroblastic transdifferentiation and collagen gene expression through the Rho-kinase dependent signaling pathway in rat mesangial cells. 1892 59

In a rat model of long-lasting pressure-overload hypertrophy, we investigated whether changes in the relative expression of myocardial actin isoforms are among the early signs of ventricular mechanical dysfunction before the transition toward decompensation. Forty-four rats with infrarenal aortic banding (AC rats) were studied. Hemodynamic parameters were measured 1 mo (AC(1) group; n = 20) or 2 mo (AC(2); n = 24) after aortic ligature. Then subgroups of AC(1) and AC(2) left ventricles (LV) were used to evaluate 1) LV anatomy and fibrosis (morphometry), 2) expression levels (immunoblotting) and spatial distribution (immunohistochemistry) of alpha-skeletal actin (alpha-SKA), alpha-cardiac actin (alpha-CA), and alpha-smooth muscle actin (alpha-SMA), and 3) cell mechanics and calcium transients in enzimatically isolated myocytes. Although the two AC groups exhibited a comparable degree of hypertrophy (+30% in LV mass; +20% in myocyte surface) and a similar increase in the amount of fibrosis compared with control animals (C group; n = 22), a worsening of LV mechanical performance was observed only in AC(2) rats at both organ and cellular levels. Conversely, AC(1) rats exhibited enhanced LV contractility and preserved cellular contractile behavior associated with increased calcium transients. Alpha-SKA expression was upregulated (+60%) in AC(1). In AC(2) ventricles, prolonged hypertension also induced a significant increase in alpha-SMA expression, mainly at the level of arterial vessels. No significant differences among groups were observed in alpha-CA expression. Our findings suggest that alpha-SKA expression regulation and wall remodeling of coronary arterioles participate in the development of impaired kinetics of contraction and relaxation in prolonged hypertension before the occurrence of marked histopathologic changes.
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PMID:Modulation of actin isoform expression before the transition from experimental compensated pressure-overload cardiac hypertrophy to decompensation. 1925 91

Recently, kidney fibrosis following transplantation has become recognized as a main contributor of chronic allograft nephropathy. In transplantation, transient ischemia is an inescapable event. Reactive oxygen species (ROS) play a critical role in ischemia and reperfusion (I/R)-induced acute kidney injury, as well as progression of fibrosis in various diseases such as hypertension, diabetes, and ureteral obstruction. However, a role of ROS/oxidative stress in chronic kidney fibrosis following I/R injury remains to be defined. In this study, we investigated the involvement of ROS/oxidative stress in kidney fibrosis following kidney I/R in mice. Mice were subjected to 30 min of bilateral kidney ischemia followed by reperfusion on day 0 and then administered with either manganese (III) tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP, 5 mg/kg body wt ip), a cell permeable superoxide dismutase (SOD) mimetic, or 0.9% saline (vehicle) beginning at 48 h after I/R for 14 days. I/R significantly increased interstitial extension, collagen deposition, apoptosis of tubular epithelial cells, nitrotyrosine expression, hydrogen peroxide production, and lipid peroxidation and decreased copper-zinc SOD, manganese SOD, and glucose 6-phosphate dehydrogenase activities in the kidneys 16 days after the procedure. MnTMPyP administration minimized these postischemic changes. In addition, MnTMPyP administration significantly attenuated the increases of alpha-smooth muscle actin, PCNA, S100A4, CD68, and heat shock protein 47 expression following I/R. We concluded that kidney fibrosis develops chronically following I/R injury, and this process is associated with the increase of ROS/oxidative stress.
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PMID:Reactive oxygen species/oxidative stress contributes to progression of kidney fibrosis following transient ischemic injury in mice. 1945 20

beta-catenin functions as both a structural protein and a transcriptional activator. In this study, we examined the expression of beta-catenin in human cirrhotic livers, and administered adenoviruses carrying the beta-catenin or DeltaTCF4 genes to cirrhotic rats to investigate the role of beta-catenin in the development of liver cirrhosis development. beta-catenin expression was associated with liver cirrhosis development in cirrhotic human and rat liver. beta-catenin adenovirus was capable of accelerating cirrhosis progress but this progression was unaffected by administration of DeltaTCF4 adenovirus. beta-catenin was mainly located in the intercellular regions between liver cells and was highly concentrated in the hepatic sinusoid wall, where alpha-smooth muscle actin (SMA) was also mainly distributed. The binding of beta-catenin to alpha-SMA was also increased in cirrhotic liver. Portal vein blood pressure was significantly increased in the group administered beta-catenin adenovirus, but not in that receiving DeltaTCF4 adenovirus. These results suggest that high concentrations of beta-catenin at the hepatic intercellular membrane and the hepatic sinusoid wall contribute to hepatic hyperpiesia in liver cirrhosis patients. beta-catenin functions as a structural molecule, but not as a signaling molecule, during liver cirrhosis development.
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PMID:Overexpression of beta-catenin is responsible for the development of portal hypertension during liver cirrhosis. 1946 46

Significant reduction of renal mass initiates a series of hemodynamic and nonhemodynamic events which lead to proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal failure. Lipid mediators derived from fatty acids participate in regulation of renal hemodynamic and nonhemodynamic processes that influence progression of renal disease. Composition of cellular fatty acids and hence related signaling responses are influenced by their dietary contents. Consumption of omega-3 fatty acids (O-3FA) has proven effective in mitigating atherosclerosis. We tested the hypothesis that O-3FA supplementation may retard progression and attenuate upregulation of pathways involved in oxidative stress, inflammation, and fibrosis in rats with renal mass reduction. Sprague-Dawley rats were subjected to 5/6 nephrectomy [chronic renal failure (CRF)] and randomly assigned to the untreated and O-3FA-treated (0.3 g.kg(-1).day(-1) by gastric gavage for 12 wk) groups. Sham-operated rats served as controls. The untreated CRF rats exhibited proteinuria, hypertension, azotemia, upregulations of renal tissue NAD(P)H oxidase, MCP-1, COX-2, PAI-1, TGF-beta, Smad2, alpha-smooth muscle actin, fibronectin, and hepatocyte growth factor, activation of ERK1/2 and NF-kappaB, downregulation of Smad7, intense mononuclear leukocyte infiltration, tubulointerstitial fibrosis, and glomerulosclerosis. O-3FA supplementation significantly lowered COX-2, NAD(P)H oxidase (NOX-4, gp91(phox), p47(phox), p22(phox)), PAI-1, TGF-beta, connective tissue growth factor, alpha-smooth muscle actin, fibronectin, Smad2, and MCP-1, raised Smad7, and attenuated ERK1/2 and NF-kappaB activation, tubulointerstitial fibrosis, and inflammation. Thus, long-term O-3FA supplementation can reduce or reverse upregulation of prooxidant, proinflammatory, and profibrotic pathways and attenuate tubulointerstitial fibrosis in the remnant kidney.
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PMID:Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney. 1965 15

Fibrosis is the response of heart and other organs to injuries. Excessive fibrosis can cause organ dysfunction or even failure. Transforming-growth factor (TGF)-beta is a cytokine that induces fibroblast proliferation and increases the synthesis of a number of extracellular matrix proteins including collagens. Decorin (DCN) is a natural antagonist of TGF-beta. In the current study, we investigated the potential antifibrotic effects of DCN gene delivery by a recombinant adeno-associated viral (rAAV) vector to inhibit cardiac fibrosis in old, spontaneously hypertensive rats (SHRs), which develop severe cardiac and kidney fibrosis if without intervention. The rAAV-DCN vector was injected (at a dose of 1 x 10(11) vector genomes) via the tail vein into 5-month-old male SHRs, resulting in persistent, stable expression of DCN (up to 16 weeks). rAAV-DCN treatment significantly reduced collagen content and fibrosis in the heart and attenuated cardiomyocyte hypertrophy. Hemodynamics data at 16 weeks showed that DCN gene delivery induced a significant increase in left ventricular end-systolic pressure and maximal-minimal rate of pressure increase (+/-dp/dt(max)), but a decrease in left ventricular end-diastolic pressure (p < 0.05), compared with those of control animals. The expression of TGF-beta and alpha-smooth muscle actin, and the phosphorylation levels of Smad2 and p38 MAPK, were markedly reduced by rAAV-DCN treatment as compared with the controls. Thus, these results suggest that rAAV-mediated DCN overexpression led to the inhibition of hypertension-induced cardiac fibrosis and hypertrophy and improved cardiac function, and therefore may have therapeutic potential for organ fibrosis.
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PMID:Decorin gene delivery inhibits cardiac fibrosis in spontaneously hypertensive rats by modulation of transforming growth factor-beta/Smad and p38 mitogen-activated protein kinase signaling pathways. 1969 98

C-reactive protein (CRP) is a risk factor or biomarker for cardiovascular diseases, including hypertension. The present study investigated the functional importance of human CRP in hypertensive cardiac remodeling by a chronic infusion of angiotensin II (Ang II) into mice that express human CRP. Compared with the wild-type mice, although Ang II infusion caused an equally high systolic blood pressure, levels of human CRP were further elevated, and cardiac remodeling was markedly exacerbated in mice that express human CRP, resulting in a significant reduction in the left ventricular ejection fraction and fractional shortening and an increase in cardiac fibrosis (collagen I and III and alpha-smooth muscle actin) and inflammation (interleukin 1beta and tumor necrosis factor-alpha). The enhancement in cardiac remodeling in mice that express human CRP was associated with further upregulation of the Ang II type I receptor and transforming growth factor-beta1 and overactivation of both transforming growth factor-beta/Smad and nuclear factor-kappaB signaling pathways. Furthermore, in vitro studies in cardiac fibroblasts revealed that CRP alone was able to significantly induce expression of the Ang II type I receptor, collagen I/III, and alpha-smooth muscle actin, as well as proinflammation cytokines (interleukin 1beta and tumor necrosis factor-alpha), which was further enhanced by addition of Ang II. In conclusion, CRP is not only a biomarker but also a mediator in Ang II-mediated cardiac remodeling. Enhanced upregulation of the Ang II type I receptor and activation of the transforming growth factor-beta/Smad and nuclear factor-kappaB signaling pathways may be the mechanisms by which CRP promotes cardiac fibrosis and inflammation under high Ang II conditions.
Hypertension 2010 Apr
PMID:C-reactive protein promotes cardiac fibrosis and inflammation in angiotensin II-induced hypertensive cardiac disease. 2047 26

The phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a pivotal role in hypertension-induced vascular changes including vascular remodeling. The precise mechanisms underlying VSMC phenotypic modulation remain elusive. Here we test the role of peroxisome proliferator-activated receptor (PPAR)-gamma in the VSMC phenotypic modulation during hypertension. Both spontaneously hypertensive rat (SHR) aortas and SHR-derived VSMCs exhibited reduced PPAR-gamma expression and excessive VSMC phenotypic modulation identified by reduced contractile proteins, alpha-smooth muscle actin (alpha-SMA) and smooth muscle 22alpha (SM22alpha), and enhanced proliferation and migration. PPAR-gamma overexpression rescued the expression of alpha-SMA and SM22alpha, and inhibited the proliferation and migration in SHR-derived VSMCs. In contrast, PPAR-gamma silencing exerted the opposite effect. Activating PPAR-gamma using rosiglitazone in vivo up-regulated aortic alpha-SMA and SM22alpha expression and attenuated aortic remodeling in SHRs. Increased activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling was observed in SHR-derived VSMCs. PI3K inhibitor LY294002 rescued the impaired expression of contractile proteins, and inhibited proliferation and migration in VSMCs from SHRs, whereas constitutively active PI3K mutant had the opposite effect. Overexpression or silencing of PPAR-gamma inhibited or excited PI3K/Akt activity, respectively. LY294002 counteracted the PPAR-gamma silencing induced proliferation and migration in SHR-derived VSMCs, whereas active PI3K mutant had the opposite effect. In contrast, reduced proliferation and migration by PPAR-gamma overexpression were reversed by the active PI3K mutant, and further inhibited by LY294002. We conclude that PPAR-gamma inhibits VSMC phenotypic modulation through inhibiting PI3K/Akt signaling. Impaired PPAR-gamma expression is responsible for VSMC phenotypic modulation during hypertension. These findings highlight an attractive therapeutic target for hypertension-related vascular disorders.
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PMID:Impaired peroxisome proliferator-activated receptor-gamma contributes to phenotypic modulation of vascular smooth muscle cells during hypertension. 2021 46


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