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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular senescence is closely associated with age-related vascular disorders and is enhanced by angiotensin (Ang) II type 1 receptor stimulation. However, the role of Ang II type 2 receptor activation in vascular senescence is still an enigma. Ang II stimulation significantly increased senescence-associated beta-galactosidase activity and the level of 8-hydroxy-2'-deoxyguanosine, with enhancement of oxidative stress and expression of Ki-ras2A, p53, and p21 in vascular smooth muscle cells (VSMCs) from wild-type (Agtr2(+)) mice, whereas these effects of Ang II were enhanced in VSMCs from Ang II type 2 receptor null (Agtr2(-)) mice. Administration of an Ang II type 1 receptor blocker, valsartan, attenuated these parameters, with less effect in Agtr2(-) VSMCs. Ang II stimulation increased methyl methanesulfonate sensitive 2 (MMS2) expression in Agtr2(+) VSMCs but not in Agtr2(-) VSMCs. MMS2 small-interfering RNA treatment enhanced Ang II-induced senescence-associated beta-galactosidase activity and 8-hydroxy-2'-deoxyguanosine level with no significant changes in oxidative stress markers and the expression of Ki-ras2A, p53, and p21. Moreover, exposure of Agtr2(+) VSMCs to hydrogen peroxide and ultraviolet irradiation induced marked increases in senescence-associated beta-galactosidase activity and 8-hydroxy-2'-deoxyguanosine level, which were further enhanced in Agtr2(-) and MMS2 small-interfering RNA-treated Agtr2(+) VSMCs. Agtr2(+) mice exposed to x-ray irradiation showed increases in senescence-associated beta-galactosidase activity and 8-hydroxy-2'-deoxyguanosine level in the aorta, which were further exaggerated in the aorta of Agtr2(-) mice with a lower MMS2 level. These findings suggest that Ang II type 2 receptor signaling attenuates DNA damage and consequent vascular senescence at least in part through MMS2 transactivation and propose the beneficial effects of Ang II type 2 receptor stimulation with Ang II type 1 receptor blockers in age-related vascular disorders.
Hypertension 2008 May
PMID:Angiotensin II type 2 receptor deletion enhances vascular senescence by methyl methanesulfonate sensitive 2 inhibition. 1836 23

Gene therapy has become an important tool for understanding several cardiovascular diseases. In the present study we investigated the effects of endothelial nitric oxide synthase (eNOS) overexpression on renovascular hypertension. Experiments were carried out in C57BL/6 mice randomly assigned to either a two-kidney one-clip (2K1C) hypertension group or a sham-operated group. At the same time surgery was carried out, both 2K1C and sham mice received an intravenous injection of recombinant adenovirus expressing the functional gene eNOS or the reporter gene beta-galactosidase (beta-gal). Fourteen days later, arterial pressure, baroreflex sensitivity, and cardiac sympathetic and parasympathetic tone were evaluated in conscious mice. Measurement of mean arterial pressure showed arterial hypertension in 2K1C-betagal mice compared with sham-betagal mice (121 +/- 3 vs. 96 +/- 2 mm Hg, p < 0.01), which was prevented by eNOS overexpression (2K1C-eNOS 100 +/- 4 vs. sham-eNOS 99 +/- 3 mm Hg). Linear regression analysis of the reflex tachycardia response to sodium nitroprusside-induced hypotension showed that baroreflex sensitivity was significantly attenuated in 2K1C-betagal mice (5.8 +/- 0.5 vs. sham-betagal 8.0 +/- 0.8 beats.min-1 x mm Hg-1, p < 0.05), but this decrease was not prevented by eNOS overexpression (2K1C-eNOS 7.2 +/- 0.5 vs. sham-eNOS 8.8 +/- 0.7 beats x min-1 x mm Hg-1, p < 0.05). The cardiac sympathetic tone was augmented and the vagal tone was reduced in 2K1C-betagal (152 +/- 17 and 45 +/- 12 beats.min-1, respectively) compared with sham-betagal mice (112 +/- 6 and 89 +/- 7 beats.min-1, respectively), and similar results were observed in 2K1C-eNOS mice compared with sham-eNOS. The data indicate that eNOS overexpression was able to prevent the development of 2K1C renovascular hypertension in mice, without affecting other characteristic cardiovascular dysfunctions.
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PMID:Overexpression of eNOS prevents the development of renovascular hypertension in mice. 1864 95

Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR(betageo/+) mice were generated from embryonic stem (ES) cells with a gene trap integration of a beta-galactosidase-neomycin phosphotransferase (betageo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GR(betageo/+) mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin-aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GR(betageo/+) mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GR(betageo/+) mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet.
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PMID:Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet. 1869 39

Lysosomal carboxypeptidases play important roles in catabolism of proteins and peptides and in posttranslational processing of other lysosomal enzymes. The major lysosomal serine carboxypeptidase A (cathepsin A [CathA]), also known as protective protein, activates and stabilizes two other lysosomal enzymes, beta-galactosidase and neuraminidase/sialidase 1. Genetic deficiency of CathA (galactosialidosis) causes the lysosomal storage of sialylated glycoconjugates and leads to a multiorgan pathology. The galactosialidosis patients also show arterial hypertension and cardiomyopathy, conditions not predicted from the lysosomal storage of glycoconjugates. This review summarizes the experimental data suggesting that both cardiovascular pathologies associate with persisted vasoconstrictions and impaired formation of the elastic fibers triggered by the deficiency of CathA. We also discuss the homologous serine carboxypeptidases, Scpep1 and vitellogenic-like carboxypeptidase, that are secreted from endothelial cells and could potentially affect the cardiovascular system.
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PMID:Serine carboxypeptidases in regulation of vasoconstriction and elastogenesis. 1946 48

Previous studies have underlined the importance of endothelial dysfunction and microvascular occlusion in the pathogenesis of pulmonary artery hypertension (PAH). Since the endothelial progenitor cells (EPCs) are involved in maintaining endothelial homeostasis, we observed the change of peripheral EPCs in canines before and after PAH onset. PAH was induced by intra-pulmonary artery injection of dehydromonocrotaline (DHMC) in nine beagles. Before and 48 h and 6 weeks after DHMC injection, 40 ml peripheral blood was obtained from the femoral vein. Circulating EPCs were identified as CD133 + KDR + cells and numerated by fluorescence-activated cell sorter; the EPCs functional capacity was determined by in vitro tubule-forming assay. The senescence of EPCs was determined by beta-galactosidase staining. At each time point, 2 ml blood from femoral artery was obtained for arterial oxygen pressure (PaO(2)). Forty-eight hours after DHMC injection, treated beagles suffered from hypoxemia; however, both the number and the tubule-forming capacity of EPCs were transiently raised. Six weeks later, PAH was confirmed by obviously high mean pulmonary arterial pressure (20.2 +/- 1.64 vs. 11.3 +/- 2.0 mmHg, p < 0.05) and low PaO(2) (69.30 +/- 9.15 vs. 95.94 +/- 1.43 mmHg, p < 0.01) in beagles after DHMC treatment, and their EPCs exhibited a predominant decrease in either the number (206.1 +/- 26.8 vs. 632.8 +/- 42.8 cells/ml blood, p < 0.01) or the tubule-forming capacity (21.1 +/- 2.8 vs. 11.2 +/- 2.8 tubules/x200 field, p < 0.01). Additionally, senescence-associated beta-galactosidase-positive EPCs were significantly increased. Our data suggested that, after the acute stage of DHMC injury to pulmonary vessels, the EPCs from PAH beagles suffered from exhaustion and senescence.
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PMID:Senescent endothelial progenitor cells from dogs with pulmonary arterial hypertension: a before-after self-controlled study. 1963 69

The renin-angiotensin system is activated in the early phase of two-kidney, one-clip (2K-1C) hypertension. The paraventricular nucleus (PVN) integrates inputs regulating sympathetic outflow. The PVN receives inputs from plasma angiotensin II via projections from circumventricular organs and from renal afferent nerves transmitted via the nucleus tractus solitarii. Nitric oxide within the PVN may exert a sympathoinhibitory effect. These studies tested whether decreasing endogenous nitric oxide by introducing dominant negative (DN) constructs for neuronal nitric oxide synthase (nNOS) into PVN chronically augments hypertension and/or modulates baroreflex function. Male 6-week-old Sprague-Dawley rats underwent sham surgery or right renal artery clipping and placement of radiotelemetry transmitters. One week later, the PVN was injected bilaterally with 250 nl artificial cerebrospinal fluid containing 250 ng microl(-1) of RSV beta-galactosidase (beta-Gal), cytomegalovirus (CMV) wild-type (WT nNOS), or respiratory syncytial virus (RSV) haeme domain or RSV haemeRedF (DN nNOS). Haemodynamics were monitored for 5 weeks. Then left renal nerve electrodes were placed, and 2 days later the rats underwent baroreflex testing in the conscious state. The rise in mean arterial pressure (MAP) was significantly potentiated in the DN nNOS 2K-1C group beyond 15 days after PVN injection. By day 35, MAP in the 2K-1C groups was 152 +/- 6.3 (beta-Gal), 155.1 +/- 6.6 (WT nNOS) and 179 +/- 5.4 mmHg (DN nNOS; P < 0.01 versus all other groups). Sham-clipped rats remained normotensive. All groups displayed progressive bradycardia over time that was attenuated in the DN nNOS 2K-1C group. Baroreflex curves shifted to higher pressures, and baroreflex sensitivity of heart rate was diminished to a similar extent in all groups of 2K-1C rats. The baroreflex response of renal sympathetic nerve activity was preserved. The PVN tissue from DN nNOS rats had decreased dimerization of nNOS and generation of total nitric oxide. These findings indicate that chronic interference of nNOS dimerization required for generation of nitric oxide within the PVN potentiates the increase of blood pressure by modulating the sympathoexcitation that accompanies renovascular hypertension.
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PMID:Neuronal nitric oxide synthase within paraventricular nucleus: blood pressure and baroreflex in two-kidney, one-clip hypertensive rats. 2049 20


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