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)

The exact mechanisms responsible for the progression of heart failure remain unclear. We investigated the in vivo relationship between the incidence of apoptotic cell death and left ventricular function serially from the beginning of hypertension to decompensated heart failure in Dahl salt-sensitive rats. Dahl salt-resistant and Dahl salt-sensitive rats were fed on a high-salt diet from 6 weeks of age. Systolic blood pressure was recorded by the tail-cuff method every week. Cardiac function in vivo was evaluated by echocardiography and cardiac catheterization. Cardiomyocyte apoptosis was detected by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) method. The gene expression of Bax, Bcl-2 and Bcl-xL was analysed by Northern blotting. The TUNEL method revealed that the incidence of cardiomyocyte apoptosis was significantly increased in the hearts of 18-week-old Dahl salt-sensitive rats (apoptotic index 1.3 +/- 0.1%). Northern blot analysis revealed that the Bcl-xL mRNA level increased gradually during the progression towards heart failure. In conclusion, these data suggest that cardiomyocyte apoptosis is a terminal event, and plays a role as an aggravating factor in the vicious cycle of heart failure.
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PMID:Relationship between cardiomyocyte cell death and cardiac function during hypertensive cardiac remodelling in Dahl rats. 1186 74

To explore the effect of angiotensin converting enzyme (ACE) inhibitor on apoptosis in spontaneously hypertensive rats(SHR), and normotensive control rats (WKY) at different ages were used. Ramipril (1 mg.kg-1.d-1) was administered orally to male SHR from 3 or 5 weeks to 10 weeks of age. Male and age-matched untreated SHR and WKY were used as controls. Experiments determined. Apoptosis in cardiomyocytes of SHR was quantified by a maximal labeling (Lmax) method and the characteristic features of apoptosis were identified by electron microscopy (EM), in situ labeling of DNA strand breaks with terminal deoxynucleotidyl transferase mediated dUTP end labeling (TUNEL) and autoradiographic analysis of DNA fragments. The results of the quantitative method showed an age-dependent increase in apoptosis in the cardiac tissues of SHR. A significant increase in DNA breaks occurred as early as age 4 weeks and continued to increase up to a plateau at age 16 weeks in the cardiac tissue of SHR, whereas there was no significant change in apoptosis in WKY up to 64 weeks. Moreover, after the treatment of SHR with ramipril, an inhibitor of ACE, the DNA fragmentation, like BP and HW/BW, was reduced significantly (70.7%) as compared with that of untreated SHR(P < 0.01); and similar to that of the WKY (P > 0.1), the DNA ladder disappeared, which was very obvious in the untreated SHR. These studies demonstrate that ramipril can prevent the development of hypertension and myocardial hypertrophy and can inhibit the increase in the apoptosis of SHR cardiac myocytes, suggesting that apoptosis may be involved in the pathogenesis of genetic hypertension.
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PMID:[Investigation of inhibitory effect of ramipril on apoptosis in spontaneously hypertensive rats]. 1220 19

We investigated the potential neuroprotective effect of transient hypertension on neuronal cell death induced by ischemia-reperfusion. Recovery of neurons, terminally differentiated cells, is almost entirely dependent upon active transcription and repair of DNA damage. We focused on the histochemical detection of distribution of NOR (argyrophylic nucleolar proteins) reflecting nucleolar integrity, immunohistochemical detection of PARP-1 (poly(ADP-ribose) polymerase-1), MADD (mitogen-activated death domain), a protein accumulated in nucleoli upon stimulation by ischemia, the active form of caspase-3, a universal proteolytic enzyme of apoptosis. The terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP-biotin nick-end-labeling method (TUNEL) proved the presence of in situ DNA fragmentation. We used the model of transient focal cerebral ischemia in rats with occlusion of middle cerebral artery. In experimental group of rats, the transient hypertension was induced by constriction of the abdominal aorta. The period of ischemia lasted 15, 30, 60 and 120 min followed by 48 h of reperfusion. We examined the frontal lobe of the ipsilateral hemisphere for apoptosis of neurons and compared it with the intact brain tissue. In normotensive rats with transient focal cerebral ischemia, we found disintegrated nucleoli of cortical as well as subcortical neurons at all investigated periods of ischemia, whereas the neurons of intact animals showed compact nucleoli with a few satellites. Nuclear positivity for MADD and PARP-1 was apparent in the neocortex after 15 min and peaked after 30 min of ischemia. On the other hand, the subcortical neurons showed nuclear positivity after 60 and 120 min. The immunohistochemical reaction for active caspase 3 was apparent after 30 min onwards predominantly in the cortex. The TUNEL staining was distinct after 60 and 120 min. In hypertensive rats, we found nucleolar disintegration, positivity for MADD, PARP-1 and caspase 3 after 30 min cortically and subcortically, followed by TUNEL positive staining of cortical neurons after 60 and 120 min. In summary, we detected delayed activation of neuronal apoptosis in transiently hypertensive rats with focal cerebral ischemia compared to normotensive animals. The apoptotic phenotype was confirmed by a panel of complementary methods showing rapid proteolysis-nucleolar segregation, MADD, PARP-1 and caspase-3 positivity as well as ultimate DNA fragmentation proved by the TUNEL assay.
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PMID:The onset of apoptosis of neurons induced by ischemia-reperfusion injury is delayed by transient period of hypertension in rats. 1262 16

In hearts with chronic left ventricular (LV) systolic dysfunction secondary to hypertension or myocardial infarction, MAPK phosphorylation and/or activity are increased. Whether other settings of LV dysfunction not associated with ischemia-reperfusion are also characterized by increased MAPK phosphorylation or activity is unknown. After 3 wk of rapid LV pacing (400 beats/min), eight rabbits displayed clinical signs of heart failure (HF), and echocardiography revealed an increase in LV end-diastolic diameter from 15.6 +/- 0.7 (means +/- SE) to 18.8 +/- 0.7 mm and a reduced shortening fraction from 31 +/- 1to10 +/- 2% (both P < 0.05). Morphological alterations in HF included increased numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cardiomyocytes, extent of fibrosis, and cross-sectional cardiomyocyte area. Total p38 MAPK did not differ between failing and normal hearts (n = 8). However, p38 MAPK phosphorylation [164,488 +/- 29,323 vs. 43,565 +/- 14,817 arbitrary units (AU), P < 0.05, densitometry] and the activities of p38 MAPK-alpha and -beta were increased in failing compared with normal hearts (149,441 +/- 38,381 and 170,430 +/- 32,952 vs. 68,815 +/- 28,984 and 81,788 +/- 22,774 AU, respectively, both P < 0.05). In failing compared with normal hearts, total and phosphorylated JNK46 and JNK54 MAPK were increased, whereas total and phosphorylated ERK MAPK remained unchanged. In pacing-induced HF, p38 and JNK MAPK phosphorylation as well as p38 MAPK activity was increased. Further studies will have to define whether or not chronic specific blockade of MAPK activity can interfere with apoptosis/fibrosis and thereby attenuate the progression of HF.
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PMID:Stress kinase phosphorylation is increased in pacing-induced heart failure in rabbits. 1284 18

Adrenomedullin (AM) is a potent vasoactive peptide and plays an important role in cardiovascular function. In this study, we delivered the AM gene locally into the heart, using a catheter-based technique to investigate the signaling mechanism mediated by AM in protection against cardiomyocyte apoptosis induced by acute ischemia/reperfusion. After adenovirus-mediated gene delivery, highly efficient and specific expression of luciferase, green fluorescent protein, or recombinant human AM was identified in the left ventricle. Delivery of the AM gene 5 days before ischemia/reperfusion attenuated myocardial apoptosis identified by in situ dUTP nick-end labeling and DNA laddering, and the effect was blocked by the AM antagonist human calcitonin gene-related peptide (CGRP 8 to 37). AM gene transfer increased phosphorylation of Akt and glycogen synthase kinase (GSK-3beta) but reduced GSK-3beta and caspase-3 activities in the heart. The effects of AM on GSK-3beta and caspase-3 activities were blocked by CGRP (8-37) and by adenovirus containing dominant-negative Akt (DN-Akt). Furthermore, in cultured cardiomyocytes, AM also attenuated apoptosis induced by hypoxia/reoxygenation, which was accompanied by increased phospho-GSK-3beta but reduced GSK-3 and caspase-3 activities. GSK-3 and caspase-3 activities were both blocked by Ad.DN-Akt and lithium, whereas only caspase-3 was inhibited by its inhibitor Z-VAD. The effects of AM on anti-apoptosis and promoting cell viability were blocked by DN-Akt but not by constitutively active Akt, lithium, or Z-VAD. These results indicate that AM protects against cardiomyocyte apoptosis induced by ischemia/reperfusion injury through the Akt-GSK-caspase signaling pathway.
Hypertension 2004 Jan
PMID:Adrenomedullin protects against myocardial apoptosis after ischemia/reperfusion through activation of Akt-GSK signaling. 1466 48

Systemic Sclerosis (SSc) is a connective tissue disease affecting the skin and internal organs. Retinopathy has been described in patients with SSc, but cannot be distinguished from secondary changes due to concomitant hypertension. UCD 200 chickens, a well-established animal model for SSc, were used in this study to investigate the posterior ocular segment for manifestations of SSc. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling was applied to detect endothelial cell (EC) apoptosis, a condition previously shown to represent the first step in SSc pathogenesis in humans and to be present in the skin and the involved internal organs of UCD 200 chickens in the acute stage. Our study showed a complete absence of EC apoptosis in the pecten and choroidal vessels of UCD 200 chickens in the acute stage. Ophthalmoscopy, biomicroscopy and histology revealed normal structures of the pecten, retina and choroid in the chronic stage. In summary, we showed that there is no primary involvement of the posterior ocular segment in avian SSc. SSc of UCD 200 chickens closely mimics human SSc, presenting all the clinical, serological and histological disease manifestations seen in the human counterpart. Therefore, our data raise serious doubts about primary posterior ocular involvement in human SSc. However, fundal examinations in patients with SSc may have their justification for assessment of hypertensive retinopathy.
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PMID:Investigations for retinopathy in an avian model for systemic sclerosis. 1518 3

The morphology of cerebral cortex was investigated in male spontaneously hypertensive rats (SHR) aged 2, 4 and 6 months (pre-hypertensive, developing hypertension and established hypertension respectively) and in age-matched normotensive Wistar-Kyoto (WKY) rats using quantitative microanatomical techniques. Analysis included frontal and occipital cortex as a paradigm of motor and sensory cerebrocortical areas respectively. Values of systolic pressure were slightly higher in 2-month-old SHR compared to age-matched WKY rats and augmented progressively with increasing age in SHR. In frontal cortex of SHR a decrease of nerve cell number and of cortical volume was observed in layers V and VI of 4- and 6- month-old SHR, and in layers I-IV of 6- month-old SHR. In occipital cortex a decrease of the number of nerve cells and of cortical volume was observed in layers V and VI of 2-, 4-, 6- month-old SHR, and in layers I-IV of 6-month-old SHR. Numerical decrease of neurons in SHR affected to a greater extent occipital cortex than frontal cortex. An increase in the number of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes (hyperplasia) as well as in the mean immune reaction area (hypertrophy) was found in the two cerebrocortical areas investigated of 6-month-old SHR. The occurrence of apoptosis and/or necrosis identified using the terminal deoxyribo-nucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labeling (TUNEL) technique was also observed in frontal and occipital cortex of 6-month-old SHR, but not of younger cohorts. These findings indicate the development of microanatomical changes in the cerebral cortex of SHR, the extent of which increases parallel with the progression of hypertension. The occurrence of cerebrocortical apoptosis and/or necrosis as well as the obvious astrogliosis occurring in established hypertension may account for the increased risk of vascular dementia that represents a specific trait of complicated hypertension.
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PMID:The cerebral cortex of spontaneously hypertensive rats: a quantitative microanatomical study. 1519 85

Apoptosis is a mechanism of cell death implicated in the pathogenesis of alcohol-induced organ damage. Experimental studies have suggested alcohol-mediated apoptosis in the cardiac muscle, and there is evidence of skeletal muscle apoptosis in long-term high-dose alcohol consumers. The relation between skeletal and cardiac muscle damage in alcoholism led us to consider the pathogenic role of apoptosis in alcoholic dilated cardiomyopathy. We evaluated apoptosis in the hearts of individuals with long-term alcoholism (n = 19), of those with long-standing hypertension (n = 20), and of those with no known disease as control subjects (n = 7). Alcohol consumption measurement, heart function evaluation, and myocardial immunohistochemical and morphometric analysis were performed. Apoptosis was evaluated with deoxyribonucleotidyl transferase-mediated dUTP-biotin nick end-labeling assay, and BAX and BCL-2 expressions were used to detect induction of and protection from proapoptotic mechanisms, respectively. Hearts from patients with a history of alcoholism showed apoptotic indexes similar to those of organs from hypertensive donors. Subjects with structural heart damage of alcoholic or hypertensive origin showed higher apoptotic indexes in deoxyribonucleotidyl transferase-mediated dUTP-biotin nick end-labeling, BAX, and BCL-2 assays as compared with control subjects (P < .001 for all). Moreover, New York Heart Association class I alcoholic patients displayed higher BAX and BCL-2 expressions as compared with control subjects. We conclude that apoptosis is present to a similar degree in the heart muscle of high-dose alcohol consumers and long-standing hypertensive subjects and is related to structural damage. Proapoptotic mechanisms are activated in alcoholic patients without heart damage.
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PMID:Evidence of apoptosis in alcoholic cardiomyopathy. 1686 74

Lipocalin-type prostaglandin D(2) synthase (L-PGDS) is a highly glycosylated protein found in several body fluids. Elevated L-PGDS levels have been observed in the serum of patients with renal impairment, diabetes mellitus, and hypertension. Recently, we demonstrated the ability of L-PGDS to induce apoptosis in a variety of cell types including epithelial cells, neuronal cells, and vascular smooth muscle cells (VSMCs). The aim of this study was to investigate the effect several site-directed mutations had on L-PGDS-induced apoptosis in order to identify potential sites of regulation. Point mutations created in a glycosylation site (Asn51), a protein kinase C phosphorylation site (Ser106), and the enzymatic active site (Cys65) all inhibited L-PGDS-induced apoptosis as determined by both terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) and caspase3 activity. We also compared the L-PGDS isoforms present in GK rat serum to WKY control serum using two-dimensional gel electrophoresis and observed distinct differences which vanished after PNGase F glycolytic digestion. We conclude that post-translational modification of L-PGDS, by either glycosylation or phosphorylation, enhances its apoptotic activity and inhibits VSMC hyperproliferation and postulate that this process is altered in type 2 diabetes.
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PMID:Post-translational modification regulates prostaglandin D2 synthase apoptotic activity: characterization by site-directed mutagenesis. 1725 69

Angiotensin II exerts its central nervous system effects primarily via its receptors AT1 and AT2, and it participates in the pathogenesis of ischemia via AT1. The selective AT1 receptor blocker (ARB) is used in the hypertension treatment, and it exerts a variety of pleiotropic effects, including antioxidative, antiapoptotic, and anti-inflammatory effects. In this study, we investigated the therapeutic effect of the ARB telmisartan in experimental intracerebral hemorrhage (ICH) in normotensive rats. ICH was induced via the collagenase infusion or autologous blood injection. Either telmisartan at 30 mg/kg/dose or phosphate-buffered saline was orally administered 2 h after ICH induction. We evaluated hemorrhage volume, brain water content, and functional recovery, and we performed the histological analysis for terminal deoxynucleotidyl transferase dUTP nick-end labeling, leukocyte infiltration, and microglia activation. A variety of intracellular signals, in terms of oxidative stress, apoptotic molecules, and inflammatory mediators, were also measured. Telmisartan reduced hemorrhage volume, brain edema, and inflammatory or apoptotic cells in the perihematomal area. Telmisartan was noted to induce the expression of endothelial nitric-oxide synthase and peroxisome proliferator-activated receptor gamma and decrease oxidative stress, apoptotic signal, tumor necrosis factor-alpha, and cyclooxygenase-2 expression. The telmisartan-treated rats exhibited less pronounced neurological deficits and recovered better. Thus, telmisartan seems to offer neural protection, including antiapoptosis, anti-inflammatory, and antioxidant benefits in the intracerebral hemorrhage rat model.
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PMID:Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. 1753 8


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