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)

Whereas the protein product of the Bcl-2 gene inhibits apoptosis, the protein product of the Bax gene acts as a promoter of apoptosis. To gain insight into the regulation of apoptosis in vascular smooth muscle cells in arterial hypertension, we investigated the expression of the proteins Bcl-2 and Bax in small intramyocardial arteries of 36-week-old normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In addition, 16-week-old SHR were treated for 20 weeks with the angiotensin-converting enzyme inhibitor quinapril and killed at 36 weeks of age. We measured the percentages of smooth muscle cells expressing these proteins using monoclonal antibodies and the avidin-biotin immunoperoxidase method. Compared with WKY, untreated SHR exhibited increased (P<.001) Bcl-2 expression and similar Bax expression. Values of Bcl-2 measured in quinapril-treated SHR were significantly lower than values measured in untreated SHR and similar to values measured in WKY. Quinapril-treated SHR showed higher (P<.001) Bax expression than WKY and untreated SHR. Bcl-2 expression was directly correlated with systolic pressure. Inverse correlations were found between the expression of Bax and the activities of both cardiac and circulating angiotensin-converting enzyme. These findings suggest that smooth muscle cell apoptosis might be inhibited in small arteries of adult SHR as a consequence of an excess of the protein Bcl-2. In addition, our results suggest that chronic angiotensin-converting enzyme inhibition might restore the susceptibility to apoptosis in these cells through stimulation of the protein Bax.
Hypertension 1997 Mar
PMID:Is the regulation of apoptosis altered in smooth muscle cells of adult spontaneously hypertensive rats? 905 95

An association of increased apoptosis with overactivity of the local angiotensin-converting enzyme has been reported in cells from the left ventricle of adult rats with spontaneous hypertension (SHR). To gain insight into the regulation of cardiac apoptosis in arterial hypertension, we investigated the expression of the proteins Bcl-2 (an inhibitor of apoptosis) and Bax (an inducer of apoptosis) in the left ventricle of 30-week-old normotensive Wistar-Kyoto rats (WKY), SHR, and SHR treated with the angiotensin II type 1 receptor (AT1) antagonist losartan (20 mg x kg(-1) x d(-1)) during 14 weeks before death. The density of apoptotic cells was assessed by direct immunoperoxidase detection of biotin-labeled deoxyuridin nucleotides. The expression of Bcl-2 and Bax was assessed by Western blot analysis. Compared with WKY, untreated SHR exhibited increased (P<0.05) apoptosis, increased (P<0.01) Bax, and similar Bcl-2. The Bcl-2/Bax ratio (an inverse index of cell susceptibility to apoptosis) was lower (P<0.05) in untreated SHR than in WKY. The chronic administration of losartan was associated with the normalization of apoptosis, Bax expression, and the Bcl-2/Bax ratio in treated SHR. No changes in the expression of Bcl-2 were observed in these rats after treatment. No significant changes in the apoptotic density were observed between treated SHR with normal blood pressure and treated SHR with abnormally high blood pressure at the end of the treatment period. These results suggest that an association exists between increased apoptosis and overexpression of Bax oncoprotein in cells from the left ventricle of adult SHR. Chronic blockade of AT1 receptors prevents Bax overexpression and normalizes apoptosis in the left ventricle of SHR independently of its hemodynamic effect. On the basis of our findings, it can be proposed that the interaction of angiotensin II with its AT1 receptors may participate in the stimulation of Bax protein, which in turn renders cells from the left ventricle of SHR more susceptible to apoptosis.
Hypertension 1998 Aug
PMID:Overexpression of Bax protein and enhanced apoptosis in the left ventricle of spontaneously hypertensive rats: effects of AT1 blockade with losartan. 971 55

Increased apoptosis has been demonstrated in various forms of human and experimental cardiovascular disease. The role of this phenomenon in the vasculature in different models of hypertension is unclear. In hypertension, regression of vessel wall hypertrophy/hyperplasia or remodeling in response to various antihypertensive drugs may be mediated in part by apoptosis. This study examined vascular smooth muscle apoptosis in spontaneously hypertensive rats (SHR), in which it may presumably counterbalance vascular wall growth. Angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers induce regression of the vascular wall in hypertension. Therefore, we investigated the effect of the ACE inhibitor enalapril and the dihydropyridine calcium channel blocker amlodipine on apoptosis in blood vessels of SHR to determine whether part of the growth inhibitory effect of these drugs is mediated by apoptosis. This was performed by detection and measurement of DNA fragmentation using DNA laddering and examining aortic histologic sections with in situ end-labeling (terminal deoxynucleotide transferase-mediated dUTP-nick labeling [TUNEL]). Ten-week-old SHR were treated for 12 weeks with 10 mg/kg per day of enalapril and 20 mg/kg per day of amlodipine. Blood pressure was significantly reduced by enalapril and amlodipine (P < .01). Cross-sectional area of aorta was significantly increased (3.34+/-0.15 mm2) in SHR compared to that of Wistar-Kyoto (WKY) control rats (1.17+/-0.07 mm2, P < .01). The cross-sectional area of the aorta was significantly smaller in enalapril-treated SHR (2.42+/-0.12 mm2, P < .05) compared to untreated SHR, and almost normalized by amlodipine (1.65+/-0.31 mm2, P < .01). Apoptosis characterized using terminal deoxynucleotidyl transferase to radiolabel 3'-OH ends of fragmented DNA extracted from aorta, showed presence of fragmented labeled DNA as "DNA laddering," a hallmark of apoptosis. SHR had increased apoptosis (341+/-25 pixels/microg DNA) compared to WKY controls (206+/-13 pixels/microg DNA, P < .01). Apoptosis was six- to eightfold greater in aorta of enalapril and amlodipine-treated SHR (P < .01). These results were confirmed by in situ end-labeling of fragmented DNA in aortic histologic sections. Western blot quantification of Bax and Bcl-2 (pro- and antiapoptotic gene products, respectively) showed higher Bax and lower Bcl-2 expression, and accordingly increased the Bax-to-Bcl-2 ratio in aorta from SHR treated with enalapril or amlodipine in comparison to untreated SHR. In conclusion, enhanced apoptosis is present in aorta of SHR, possibly as a homeostatic mechanism counterbalancing growth. Antihypertensive agents such as the ACE inhibitor enalapril and the calcium antagonist amlodipine may cause regression or inhibition of vascular wall growth in SHR partly through enhanced apoptosis, which may contribute to the antihypertensive effects of these drugs.
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PMID:Apoptosis in vasculature of spontaneously hypertensive rats: effect of an angiotensin converting enzyme inhibitor and a calcium channel antagonist. 975 97

In 30 patients with essential hypertension and 30 healthy control subjects, we evaluated blood concentrations of B cell leukemia-2 (bcl-2), a protooncogene that can reduce apoptosis. Bcl-2 concentrations were higher in hypertensive than in normotensive subjects. The increase in pressure due to a cold pressor test caused a further increase in blood bcl-2 concentrations, in both hypertensive and normotensive subjects. Treatment of hypertensive patients with hypotensive drugs caused a reduction in bcl-2 concentrations, which was more marked after administration of lisinopril than of nifedipine. The results suggest that concentrations of bcl-2 are increased in patients with hypertension, which could be an important factor in cell proliferation underlying posthypertensive vascular remodeling. Moreover, lisinopril and nifedipine appear to be capable of reducing bcl-2 concentrations, with potentially beneficial effects on vascular modifications in patients with hypertension.
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PMID:Reduced bcl-2 concentrations in hypertensive patients after lisinopril or nifedipine administration. 1007 88

The bcl-2 and caspase families are important regulators of programmed cell death in experimental models of ischemic, excitotoxic, and traumatic brain injury. The Bcl-2 family members Bcl-2 and Bcl-xL suppress programmed cell death, whereas Bax promotes programmed cell death. Activated caspase-1 (interleukin-1beta converting enzyme) and caspase-3 (Yama/Apopain/Cpp32) cleave proteins that are important in maintaining cytoskeletal integrity and DNA repair, and activate deoxyribonucleases, producing cell death with morphological features of apoptosis. To address the question of whether these Bcl-2 and caspase family members participate in the process of delayed neuronal death in humans, we examined brain tissue samples removed from adult patients during surgical decompression for intracranial hypertension in the acute phase after traumatic brain injury (n=8) and compared these samples to brain tissue obtained at autopsy from non-trauma patients (n=6). An increase in Bcl-2 but not Bcl-xL or Bax, cleavage of caspase-1, up-regulation and cleavage of caspase-3, and evidence for DNA fragmentation with both apoptotic and necrotic morphologies were found in tissue from traumatic brain injury patients compared with controls. These findings are the first to demonstrate that programmed cell death occurs in human brain after acute injury, and identify potential pharmacological and molecular targets for the treatment of human head injury.
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PMID:Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. 1022 25

Hypertension results in microvascular rarefaction or disappearance of microvessels. In the present study, we investigated the pathogenic role of apoptosis in hypertension-induced rarefaction of heart arterioles and capillaries of spontaneously hypertensive rats (SHR). Experiments were performed on hearts from 6-week-old, 16-week-old, and 30-week-old SHR (n = 30 rats) (SHR6, SHR16, SHR30). We used as controls 6-week-old, 16-week-old, and 30-week-old normotensive rats (WKY) (n = 30 rats) (WKY6, WKY16, WKY30). We analyzed the expression of c-myc, bcl-2, and bax and in situ end-labeling DNA fragmentation in vascular smooth muscle cells of arterioles and endothelial cells of arterioles and capillaries. Endothelial cells of capillaries and endothelial and smooth muscle cells of arterioles of hypertensive animals (SHR) express more Bax protein and Myc protein than their respective normotensive controls by margins that were statistically significant. The SHR30 group expressed the lowest levels of Bcl-2 protein by a margin that was statistically significantly different from WKY30. We did not find evidence of apoptosis in arterioles or capillaries on the basis of in situ end-labeling. However, our results indicated that alterations in the expression of members of the Bcl-2 family of proteins and Myc protein occurred in smooth muscle cells and endothelial cells of arterioles and capillaries of SHR. In conclusion, although evidence of apoptosis in arterioles and capillaries was not found by in situ end-labeling, our findings suggest that in hypertension they may have a higher susceptibility to apoptosis, and therefore rarefaction may be a consequence of apoptosis.
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PMID:Susceptibility to apoptosis measured by MYC, BCL-2, and BAX expression in arterioles and capillaries of adult spontaneously hypertensive rats. 1048 Apr 75

We test the hypothesis that microvascular endothelial cells may undergo apoptosis in response to acute pulmonary venous hypertension. The isolated rabbit lungs were perfused in situ for 4 h with left atrial pressure of 0, 10, or 20 mmHg at a constant blood flow. Edema formation was monitored by lung weight gain. To assay for apoptosis, we performed agarose gel electrophoresis of DNA, in situ nick end labeling of DNA strand breaks, and electron microscopy. We also examined the levels of expression of Bcl-2, a suppressor of apoptosis, in microvascular endothelial cells using an immunohistochemical technique. In a vascular pressure-dependent fashion, we found apoptosis in endothelial cells of alveolar septal capillaries, as well as expression of Bcl-2 in arteriolar and venular endothelial cells. We conclude that acute pulmonary venous hypertension induces apoptosis in capillary endothelial cells but not in arteriolar and venular endothelial cells, suggesting that microvascular endothelial cell apoptosis is dependent on the levels of Bcl-2 expression and influences the formation or resolution of acute hydrostatic lung edema.
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PMID:Apoptosis in microvascular endothelial cells of perfused rabbit lungs with acute hydrostatic edema. 1065 18

Pre-eclampsia is the main cause of fetal and maternal morbidity and death associated with hypertension during complicating pregnancy. During physiological pregnancy, the immunological system undergoes secondary modifications, with an "exchange" between mother and fetus. Cytokines play an important role in the complex condition of partial fetal "rejection". It has suggested that the condition depend on immunological factors. In line with this hypothesis, apoptosis appear to play a key role in the pathophysiology of placental ischemia and the mechanism underlying this condition may be influenced by substances such as Bcl-2 which inhibits apoptosis. Neither aspirin nor calcium appear to improve maternal hypertension and proteinuria, although late ongoing trials may alter this view. At present, the condition can be resolved only by the end of pregnancy. Further studies are required in order to improve our understanding of these immunological mechanisms underlying hypertension during pregnancy, as the key to effective therapy may be their ability to "manipulate" them in an appropriate way.
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PMID:Is apoptosis cause of pre-eclampsia? 1071 Aug 17

Adrenomedullin, which was discovered as a vasodilating peptide, has been reported to be produced in various organs, in which adrenomedullin regulates not only vascular tone but also cell proliferation and differentiation in an autocrine/paracrine manner. We evaluated the effect of adrenomedullin on endothelial cell apoptosis. Human umbilical vein endothelial cells underwent apoptosis when cultured in serum-free medium. Treatment with adrenomedullin reduced the number of cells with pyknotic nuclei (Hoechst 33258 staining) and inhibited cell death (dimethylthiazol-diphenyltetrazolium bromide assay) in a dose-dependent manner. The administration of adrenomedullin did not alter the expression levels of Bcl-2 family proteins. Experiments with analogs of cAMP or a cAMP-elevating agonist demonstrated that elevation of the intracellular cAMP concentration does not mediate the antiapoptotic effect of adrenomedullin. The coadministration of N-nitro-L-arginine methyl ester (2 mmol/L), an inhibitor of nitric oxide synthase, abrogated the effect of adrenomedullin. Lower doses of sodium nitroprusside (1 to 10 micromol/L), a nitric oxide donor, mimicked the antiapoptotic effect of adrenomedullin. The antiapoptotic effect of sodium nitroprusside was not attenuated by the inhibition of soluble guanylyl cyclase with 1 micromol/L oxadiazolo-quinoxalin-1-one nor could apoptosis be inhibited by the incubation of human umbilical vein endothelial cells with 1 mmol/L 8-bromo-cGMP, a cell-permeant cGMP analog. These results indicate that adrenomedullin and nitric oxide inhibit endothelial cell apoptosis via a cGMP-independent mechanism.
Hypertension 2000 Jul
PMID:Adrenomedullin and nitric oxide inhibit human endothelial cell apoptosis via a cyclic GMP-independent mechanism. 1090 17

Previous findings have shown that hypotensive doses of losartan prevent the excess of apoptosis present in the hypertrophied left ventricle of adult spontaneously hypertensive rats (SHR). This study was designed to determine whether angiotensin II facilitates apoptosis in cardiomyocytes of adult SHR. Primary cultures of ventricular cardiomyocytes from 30-week-old normotensive Wistar-Kyoto rats (WKY) and SHR with left ventricular hypertrophy were exposed to 10(-)(9) mol/L angiotensin II for 24 hours. Apoptotic cells were assessed by terminal deoxynucleotidyl transferase assay and confirmed by Annexin V detection. The expression of Bax-alpha, Bcl-2, p53, and caspase-3 proteins was assessed by Western blot assays. The expression of BAX gene was assessed by Northern blot. Angiotensin II increased (P<0.01) cardiomyocyte apoptosis, and this effect was higher (P<0.001) in SHR cells than in WKY cells. Whereas losartan (10(-7) mol/L) blocked the apoptotic effect of the octapeptide in cells from the two strains of rats, PD123319 (10(-7) mol/L) inhibited angiotensin II-mediated apoptosis only in SHR cells. Angiotensin II stimulated (P<0.01) Bax-alpha protein, and this effect was higher (P<0.01) in SHR cells than in WKY cells. Angiotensin II did not modify Bcl-2, p53, and BAX mRNA in cells from the two strains of rats. Angiotensin II induced a similar increase (P<0.05) in the ratio caspase-3/procaspase-3 (an index of caspase-3 activation) in cardiomyocytes from the two strains of rats. The present in vitro results indicate that SHR cardiomyocytes exhibit enhanced susceptibility to angiotensin II-induced apoptosis. Ligand binding to angiotensin II type 1 and type 2 receptors leading to changes in posttranscriptional processing of Bax-alpha and accumulation of this proapoptotic protein may be involved in the abnormal response of SHR cardiomyocytes. These data support a role for angiotensin II in apoptosis observed in the left ventricle of these rats.
Hypertension 2000 Dec
PMID:Mechanisms of increased susceptibility to angiotensin II-induced apoptosis in ventricular cardiomyocytes of spontaneously hypertensive rats. 1111 26


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