Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Mechanisms of increased susceptibility to angiotensin II-induced apoptosis in ventricular cardiomyocytes of spontaneously hypertensive rats. 1111 26

Chronically hypoxic rats (exposed to 5000 m elevation for 3 weeks) develop pulmonary hypertension (PH) that is reversed upon return to normoxia and is blocked by bradykinin (BK) antagonist B9430 treatment (100 microg/kg s.c. three times per week). Treatment of rats with both the synthetic VEGF receptor-1/2 antagonist 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-indolin-2-one (SU5416) (200 mg/kg, single s.c. injection) and hypoxia (3 weeks) causes irreversible severe PH characterized by marked elevation of pulmonary artery pressure (PAP), right ventricular hypertrophy, and obliteration of pulmonary arteries by proliferating endothelial cells (EC). Between weeks I and 2 of treatment, there is increased apoptotic EC death and caspase-3 activity. The combination of hypoxia with VEGFR-1 and -2 blockade appears to cause death of normal lung EC and proliferation of an apoptosis-resistant proliferating EC phenotype. Cotreatment with BK antagonist B9430 and (or) the broad caspase inhibitor Z-Asp-2,6-dichlorobenzoyloxymethylketone (Z-Asp) (2 mg/kg three times per week) prevented development of severe PH and caused significant reduction of PAP: 39.7 +/- 4.6 mmHg in Z-Asp + SU5416, 37.1 +/- 1.2 mmHg in BK antagonist B9430 + SU5416, 27.2 +/- 0.7 mmHg in Z-Asp alone, and 36.6 +/- 3.0 mmHg in BK antagonist alone versus 48 +/- 1.7 mmHg in SU5416-treated rats and 32.8 +/-1.4 mmHg in vehicle-treated controls. The PAP correlated with the right ventricular mass. Pulmonary arteries of rats treated with Z-Asp and BK antagonist B9430 had a marked reduction of intravascular EC, yet there was still evidence of medial muscular hypertrophy, similar to that observed in chronically hypoxic rats not treated with SU5416. We conclude that EC death induced by VEGFR-2 blockade with SU5416 may trigger an EC selection process that allows for the expansion of apoptosis-resistant EC, possibly driven by mechanisms independent of VEGF and VEGFR-2.
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PMID:A bradykinin antagonist and a caspase inhibitor prevent severe pulmonary hypertension in a rat model. 1202 60

Apoptosis, a morphological form of programmed cell death required for control of cell populations, participates in reduced tissue volume associated with ventricular scarring. Prevention of apoptosis of excessive, damaged, or nonfunctioning cardiac or of infiltrating inflammatory cells is usually beneficial for the resolution of cardiac fibrosis. Angiotensin(Ang) II, the most important peptide that mediates the effects of the renin-angiotensin system, may play an important role in hypertension, hypertrophy, and interstitial fibrosis. Furthermore, AngII induced apoptosis of human venous endothelial cells, myocyte, and vascular smooth muscular cells by caspase cascade activation, and the both blockade of AngII type(AT)1 and AT2 receptor prevents AngII induced apoptosis, whereas selective agonistic stimulation of the AT2 receptor alone induces apoptosis. When AT1 or AT2 receptors are stimulated in vivo, apoptosis is enhanced in myocytes, myofibroblasts, and media smooth muscular cells. In the case of AT1 receptor stimulation, this may occur in cardiac myocytes secondary to ventricular hypertrophy. On the other hand, AT2 receptor stimulation induced apoptosis myofibroblasts associated with reduced interstitial fibrosis. Caspase-3 participates in the pathways of apoptosis triggered by in vivo AT1 and AT2 receptor stimulations.
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PMID:[Effects of angiotensin II type 1 and type 2 receptor on apoptosis]. 1239 79

The pulmonary arteries (PA) in pulmonary arterial hypertension (PAH) are constricted and remodeled;. They have suppressed apoptosis, partly attributable to suppression of the bone morphogenetic protein axis and selective downregulation of PA smooth muscle cell (PASMC) voltage-gated K+ channels, including Kv1.5. The Kv downregulation-induced increase in [K+]i, tonically inhibits caspases, further suppressing apoptosis. Mitochondria control apoptosis and produce activated oxygen species like H2O2, which regulate vascular tone by activating K+ channels, but their role in PAH is unknown. We show that dichloroacetate (DCA), a metabolic modulator that increases mitochondrial oxidative phosphorylation, prevents and reverses established monocrotaline-induced PAH (MCT-PAH), significantly improving mortality. Compared with MCT-PAH, DCA-treated rats (80 mg/kg per day in drinking water on day 14 after MCT, studied on day 21) have decreased pulmonary, but not systemic, vascular resistance (63% decrease, P<0.002), PA medial thickness (28% decrease, P<0.0001), and right ventricular hypertrophy (34% decrease, P<0.001). DCA is similarly effective when given at day 1 or day 21 after MCT (studied day 28) but has no effect on normal rats. DCA depolarizes MCT-PAH PASMC mitochondria and causes release of H2O2 and cytochrome c, inducing a 10-fold increase in apoptosis within the PA media (TUNEL and caspase 3 activity) and decreasing proliferation (proliferating-cell nuclear antigen and BrdU assays). Immunoblots, immunohistochemistry, laser-captured microdissection-quantitative reverse-transcription polymerase chain reaction and patch-clamping show that DCA reverses the Kv1.5 downregulation in resistance PAs. In summary, DCA reverses PA remodeling by increasing the mitochondria-dependent apoptosis/proliferation ratio and upregulating Kv1.5 in the media. We identify mitochondria-dependent apoptosis as a potential target for therapy and DCA as an effective and selective treatment for PAH.
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PMID:Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. 1537 7

Bradykinin is an important modulator of endothelial cell function and has also a powerful cardioprotective effect. Here we report that treatment of severely pulmonary hypertensive rats (that recapitulate several of the physiological and pathological characteristics of the human pulmonary vascular disease, including dramatic right ventricular hypertrophy, pericardial effusion and death) with a newly synthesized long-acting bradykinin B2 receptor agonist B9972 caused reduction of the pulmonary artery pressure (PAP=51+/-2.0 versus 68+/-2.8 of untreated animals) and of right ventricular hypertrophy (Rv/Lv+S=0.55+/-0.02 versus 0.73+/-0.03 of untreated rats) and activation of Akt. Long-term stimulation with B9972 in our animal model of SPH resulted in decreased expression of the B2 receptor in lung vasculature. Treatment with B9972 decreased the number of plexiform lesions in the lungs by inducing cell apoptosis in the obliterated vessels and by restoring caveolin-1 expression. B9972 also promoted eNOS activation. In vitro B9972 caused activation of caspase-3 as well as Erk and induction of prostacyclin production in rat pulmonary microvascular EC. Taken together our data suggest that a stable bradykinin B2 agonist B9972 demonstrates the capacity to reduce severe pulmonary hypertension, right ventricular hypertrophy and induce apoptosis of hyperproliferative cells in pre-capillary pulmonary arterioles.
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PMID:Treatment of severe pulmonary hypertension: a bradykinin receptor 2 agonist B9972 causes reduction of pulmonary artery pressure and right ventricular hypertrophy. 1587 94

Disruption of leptin signaling is associated with obesity, heart failure, and cardiac hypertrophy, but the role of leptin in cardiac myocyte apoptosis is unknown. We tested the hypothesis that apoptosis increases in leptin-deficient ob/ob and leptin-resistant db/db mice and is associated with aging and left ventricular hypertrophy, increased DNA damage, and decreased survival. We studied young (2- to 3-month-old) and old (12- to 14-month-old) ob/ob and db/db mice and wild-type (WT) controls (n=2 to 4 per group). As expected, ventricular wall thickness and heart weights were similar among young ob/ob, db/db, and WT mice, but higher in old ob/ob and db/db versus old WT. Young ob/ob and db/db showed markedly elevated apoptosis by TUNEL staining and caspase 3 levels compared with WT. Differences in apoptosis were further accentuated with age. Leptin treatment significantly reduced apoptosis in ob/ob mice both in intact hearts and isolated myocytes. Tissue triglycerides were increased in ob/ob hearts, returning to WT levels after leptin repletion. Furthermore, the DNA damage marker, 8oxoG (8-oxo-7,8-dihydroguanidine), was increased, whereas the DNA repair marker, MYH glycosylase, was decreased in old ob/ob and db/db compared with old WT mice. Both ob/ob and db/db mice had decreased survival compared with WT mice. We conclude that leptin-deficient and leptin-resistant mice demonstrate increased apoptosis, DNA damage, and mortality compared with WT mice, suggesting that normal leptin signaling is necessary to prevent excess age-associated DNA damage and premature mortality. These data offer novel insights into potential mechanisms of myocardial dysfunction and early mortality in obesity.
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PMID:Cardiac myocyte apoptosis is associated with increased DNA damage and decreased survival in murine models of obesity. 1633 84

Severe pulmonary hypertension (SPH) is characterized by precapillary arteriolar lumen obliteration, dramatic right ventricular hypertrophy, and pericardial effusion. Our recently published rat model of SPH recapitulates major components of the human disease. We used this model to develop new treatment strategies for SPH. SPH in rats was induced using VEGF receptor blockade in combination with chronic hypoxia. A large variety of drugs used in this study, including anticancer drugs (cyclophosphamide and paclitaxel), the angiotensin-converting enzyme inhibitor lisinopril, the antiangiogenic agent thalidomide, and the peroxisome proliferator-actived receptor-gamma agonist PGJ2, failed to decrease mean pulmonary artery pressure (PAP) or right ventricular hypertrophy. In contrast, treatment of rats with established SPH with simvastatin markedly reduced mean PAP and right ventricular hypertrophy, and this reduction was associated with caspase-3 activation and pulmonary microvascular endothelial cell apoptosis. Simvastatin partially restored caveolin-1, caveolin-2, and phospho-caveolin expression in vessel walls. In rat primary pulmonary microvascular endothelial cells, simvastatin induced caspase 3 activation and Rac 1 expression while suppressing Rho A and attenuated levels of Akt and ERK phosphorylation. We conclude that simvastatin is effective in inducing apoptosis in hyperproliferative pulmonary vascular lesions and could be considered as a potential drug for treatment of human SPH.
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PMID:Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. 1669 53

The present study aimed to assess the effects of a COX-2 inhibitor, celecoxib, a HMG-CoA reductase inhibitor, atorvastatin, and the association of both on monocrotaline (MC)-induced pulmonary hypertension in rats. Celecoxib (Cib, 25 mg kg(-1) day(-1)), atorvastatin (AS, 10 mg kg(-1) day(-1)) or vehicle, were given orally, separately or in combination, for 26 days to Wistar male rats injected or not with MC (60 mg/kg intraperitoneally). At 4 weeks, MC-injected rats developed a severe pulmonary hypertension, with an increase in lung to body weight ratio (L/BW), right ventricular pressure (RVP in mmHg, 31 +/- 3 and 14 +/- 1 for MC and control groups, respectively, P < 0.05) and right ventricle/left ventricle + septum weight ratio (RV/LV+S) associated with a decrease in acetylcholine- and sodium-nitroprusside-induced pulmonary artery vasodilation in vitro. Hypertensive pulmonary arteries exhibited an increase in wall thickness (wall thickness to external diameter ratio, 0.42 +/- 0.01 vs 0.24 +/- 0.01 for MC and control groups, respectively, P < 0.001). Whole lung eNOS expression was decreased, and an increase in apoptosis, evaluated by cleaved caspase-3 expression, was evidenced by Western blotting. Cib (RVP in mmHg, 19 +/- 3 and 31 +/- 3 for MC+Cib and MC groups, respectively, P < 0.05), but neither AS nor AS+Cib significantly limited the development of pulmonary hypertension (P < 0.05), although the three treatments exhibited protective effects against MC-induced lung and right ventricle hypertrophy evaluated by L/BW and RV/(LV+S) ratios, respectively (P < 0.05). AS, Cib and AS+Cib treatments reduced MC-induced thickening of small intrapulmonary artery wall (0.42 +/- 0.01, 0.24 +/- 0.01, 0.26 +/- 0.01 and 0.28 +/- 0.01 for MC, MC+AS, MC+Cib and MC+AS+Cib groups, respectively, P < 0.001). In control rats, Cib reduced acetylcholine-induced pulmonary artery vasorelaxation. Treatment of MC rats by either Cib or AS did not modify acetylcholine-induced pulmonary artery relaxation, whereas combination of both drugs significantly worsened it (P < 0.05). AS, but neither Cib nor the combination of both, prevented apoptosis (AS, P < 0.05) and partially restored eNOS expression (AS, P < 0.05) in whole lung of MC rats. In conclusion, celecoxib exhibited beneficial effects against the development of monocrotaline-induced pulmonary artery hypertension and right ventricular hypertrophy. These beneficial effects of celecoxib might be, at least partly, explained by its effects on pulmonary artery thickening and pulmonary hypertrophy, even if it did not show any effect on pulmonary artery vasorelaxation and whole lung eNOS expression or apoptosis. The combination of celecoxib and atorvastatin was unable to prevent MC-induced pulmonary hypertension, decreased endothelium-dependent vasorelaxation and showed a trend toward an increased in RVP that deserves further studies.
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PMID:Celecoxib but not the combination of celecoxib+atorvastatin prevents the development of monocrotaline-induced pulmonary hypertension in the rat. 1854 28

The heart of leptin-deficient ob/ob mice is characterized by pathologic left ventricular hypertrophy along with elevated triglyceride (TG) content, increased stearoyl-CoA desaturase (SCD) activity, and increased myocyte apoptosis. In the present study, using an ob/ob;SCD1(-/-) mouse model, we tested the hypothesis that lack of SCD1 could improve steatosis and left ventricle (LV) function in leptin deficiency. We show that disruption of the SCD1 gene improves cardiac function in ob/ob mice by correcting systolic and diastolic dysfunction without affecting levels of plasma TG and FFA. The improvement is associated with reduced expression of genes involved in FA transport and lipid synthesis in the heart, as well as reduction in cardiac FFA, diacylglycerol, TG, and ceramide levels. The rate of FA beta-oxidation is also significantly lower in the heart of ob/ob;SCD1(-/-) mice compared with ob/ob controls. Moreover, SCD1 deficiency reduces cardiac apoptosis in ob/ob mice due to increased expression of antiapoptotic factor Bcl-2 and inhibition of inducible nitric oxide synthase and caspase-3 activities. Reduction in myocardial lipid accumulation and inhibition of apoptosis appear to be one of the main mechanisms responsible for improved LV function in ob/ob mice caused by SCD1 deficiency.
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PMID:Loss of stearoyl-CoA desaturase 1 rescues cardiac function in obese leptin-deficient mice. 2036 35

Aging is associated with an increased incidence of heart failure, but the existence of an age-related cardiomyopathy remains controversial. Differences in strain, age and technique of measuring cardiac function differ between experiments, confounding the interpretation of these studies. Additionally, the structural and genetic profile at the onset of heart failure has not been extensively studied. We therefore performed serial echocardiography, which allows repeated assessment of left ventricular (LV) function, on a cohort of the same mice every 3 months as they aged and demonstrated that LV systolic dysfunction becomes apparent at 18 months of age. These aging animals had left ventricular hypertrophy and fibrosis, but did not have inducible ventricular tachyarrhythmias. Gene expression profiling of left ventricular tissue demonstrated 40 differentially expressed probesets and 36 differentially expressed gene ontology terms, largely related to inflammation and immunity. At this early stage of cardiac dysfunction, we observed increased cardiomyocyte expression of the pro-apoptotic activated caspase-3, but no actual increase in apoptosis. The aging hearts also have higher levels of anti-apoptotic and autophagic factors, which may have rendered protection from apoptosis. In conclusion, we describe the functional, structural and genetic changes in murine hearts as they first develop cardiomyopathy of aging.
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PMID:Cardiomyopathy of aging in the mammalian heart is characterized by myocardial hypertrophy, fibrosis and a predisposition towards cardiomyocyte apoptosis and autophagy. 2137 20


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