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)

Erythropoietin (EPO) is a hormone known to stimulate hematopoiesis. However, recent research suggests additional properties of EPO, such as protection against ischemia/reperfusion (I/R) injury in various tissues. We studied the effect of timing of EPO administration on cardioprotection during I/R in the heart. Male Sprague-Dawley rats were subjected to 45 minutes of coronary occlusion, followed by 24 hours of reperfusion. Animals were randomized to receive saline or single dose of EPO (5,000 IU/kg) either 2 hours before I/R, at the start of ischemia, or after the onset of reperfusion. The ratio of infarct area/area at risk (planimetry), left ventricular (LV) function (pressure development), and apoptosis (number of active caspase-3 positive cells) were determined after 24-hour reperfusion. Administration of EPO during different time points resulted in a 19 to 23% (P < 0.05) reduction in the infarct area/area at risk, which was accompanied by a trend toward better LV hemodynamic parameters. Apoptosis was significantly attenuated in groups treated with EPO at the start of ischemia (29% reduction) and after the onset of reperfusion (38%), and to a lesser extent (16%) in the group pre-treated with EPO. Thus, in vivo administration of EPO at different time points protects the myocardial structure and preserves cardiac function during I/R. Cardioprotective effect of EPO is associated with inhibition of apoptosis.
J Cardiovasc Pharmacol 2004 Oct
PMID:Timing of erythropoietin treatment for cardioprotection in ischemia/reperfusion. 1545 56

Binge drinking of alcohol causes cardiac dysfunction in some people. The mechanism remains unclear. This study was designed to investigate high doses of alcohol-induced oxidative stress and apoptosis in cardiomyocytes and protective effects of antioxidants. Cardiomyocytes isolated from 1- to 2-day-old Sprague-Dawley rats were treated with ethanol at doses of 0 mM, 50 mM, 100 mM, and 200 mM for 24 hours. Vitamin E (1 mM) and vitamin C (0.2 mM) were added to medium 1 hour before addition of ethanol. Results showed typical apoptosis: chromatin condensation, membrane blebbing, shrinkage, and cytoplasm condensation. Apoptosis is concentration-dependent in the range of 0 to 100 mM ethanol (apoptosis rates were respectively 0.68%, 2.03%, and 9.66% at ethanol concentration of 0 mM, 50 mM, and 100 mM). Necrotic cells became greatly increased in the 200 mM ethanol-treated group. Intracellular production of reactive oxygen intermediates increased as mitochondrial membrane potential decreased after ethanol treatment. Cytochrome c was found to be greater in the cytosol of the ethanol-treated groups. Activity of caspase-3 was higher in ethanol-treated groups (P < 0.05). Both vitamin E and vitamin C inhibited oxidative stress and myocyte apoptosis in ethanol-treated groups (P < 0.05). In conclusion, our data indicated that acute high-dose ethanol treatment primarily induces cardiomyocyte apoptosis at concentration up to 100 mM while necrosis is predominate at 200 mM. The underlying mechanism appears to involve mitochondrial damage via an increase in oxidative stress and releasing cytochrome c, which activates caspases that initiate chromatin fragmentation and apoptosis. Antioxidants, to a large extent, inhibit oxidative stress and apoptosis induced by ethanol.
J Cardiovasc Pharmacol 2004 Dec
PMID:Oxidative stress and apoptosis in cardiomyocyte induced by high-dose alcohol. 1555 Jul 90

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases, although the mechanism leading to vascular dysfunction is not clear. The aim of this study was to examine the effect of homocysteine (Hcy) on oxi-dative stress and apoptosis in human umbilical vein endothelial cells (HUVECs). HUVECs were challenged for 24 h with Hcy (10 microM-3 mM) in the presence of various stress signaling inhibitors, including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin (100 microM), the p38 mito-gen-activated protein kinase inhibitor SB203580 (2.5 microM), the extracellular signal-regulated kinase inhibitor U0126 (2.5 microM), the stress-activated protein kinase (SAPK)/c-Jun NH2-terminal kinase (JNK) inhibitor JNK inhibitor II (10 microM), and antioxidants alpha-tocopherol (5 microg/mL) and N-acetyl cysteine (NAC, 2 mM). Reactive oxygen species (ROS) were detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride staining, annexin-V phosphatidyl- serine/propidium iodide, and caspase-3 assay. NADPH oxidase and SAPK/JNK signal were evaluated with immunoblotting. Hcy significantly enhanced ROS generation and apoptosis after 24-h incubation. Apocynin prevented Hcy-induced ROS generation but only partially restored Hcy-induced apoptosis. JNK inhibitor II, alpha-tocopherol, and NAC partially reduced Hcy-induced apoptosis, although SB203580 and U0126 had no effect. Immunoblotting analysis confirmed upregulation of NADPH oxidase and SAPK/JNK signaling. Collectively, our results suggested that Hcy may induce oxidative stress and apopto-sis through an NADPH oxidase and/or JNK-dependent mechanism(s).
Cardiovasc Toxicol 2005
PMID:Possible involvement of NADPH oxidase and JNK in homocysteine-induced oxidative stress and apoptosis in human umbilical vein endothelial cells. 1573 81

While left ventricular (LV) reduction surgery (LVR) is a novel treatment for severe heart failure, alteration of signal transduction pathways by this surgery is unknown. LV endothelin-1 plays a critical role in LV remodeling following myocardial infarction (MI). Another possible mechanism of remodeling is myocardial cell loss due to apoptosis. The purpose of the present study was to determine whether the LV endothelin-1 level and apoptosis signaling change after LVR. Adult rats were divided into two groups: non-MI group and MI group, and the MI group was subjected to permanent ligation of the left anterior descending artery. Four weeks later, rats in the MI group were subjected to LVR (LVR group) or a sham operation (OMI group). Two weeks after the second operation, echocardiography revealed that LVR improved LV systolic function and remodeling. Upregulation of LV endothein-1 was detected only in the OMI group but not in the non-MI group nor in the LVR group. The percentage of terminal deoxynucleotidyl transfer-mediated end-labeling of fragmented nuclei (TUNEL)-positive cardiac myocytes was significantly higher in the OMI group than in the LVR group or the non-MI group. Western blotting of extracts from the left ventricle showed that bcl-2 and bcl-xL levels were restored and caspase-3 activation was repressed after LVR. Thus, LVR modulates the expression of endothelin-1 and apoptosis signaling in failing hearts. These alterations of signal transduction pathways might contribute to the beneficial effects of LVR on systolic function in heart failure.
J Cardiovasc Pharmacol 2004 Nov
PMID:Down-regulation of endothelin-1 and alteration of apoptosis signaling following left ventricular volume reduction surgery in heart failure of adult rats. 1583 22

An important issue in atherosclerosis is the timing of intimal microvascular formation and its relation to the initiation of plaque formation. Monocytes and endothelial cells (ECs) are important cell components in these steps. Statins not only reduce atherogenic low density lipoprotein cholesterol, they also increase high density lipoprotein-cholesterol (HDL). Although a higher concentration of statin has an anti-proliferative effect, HDL is potentially mitogenic. Therefore, we examined the opposing effects of statin, Apo-AI, HDL and HDL fractions on cell proliferation and apoptosis in monocytes and on angiogenesis in ECs. A high concentration of simvastatin inhibited monocyte proliferation as evaluated by counting cell numbers using a hematocytometer. This inhibition was mainly blocked by the HDL3 subfraction. The same concentration of simvastatin induced apoptosis as assessed by the fluorescence-labeled annexin-V method through caspase-3 activation in monocytes. HDL inhibited simvastatin-induced apoptosis. In addition, HDL blocked simvastatin-inhibited angiogenesis in an in vitro model of EC tube formation. In conclusion, the compensatory balance between the effects of statin and HDL may play an important role in the formation of atherosclerotic lesions by affecting proliferation and apoptosis in monocytes and angiogenesis in ECs.
Cardiovasc Drugs Ther 2005 Mar
PMID:Counteracting effects of high density lipoprotein-cholesterol subfractions on statin-induced growth arrest. 1602 29

The Impact Of Nicorandil in Angina (IONA) randomized trial showed a significant reduction in coronary events, in patients with stable angina treated with a KATP channel opener, nicorandil. However, the impact of nicorandil on endothelial apoptosis remains to be examined. We tested the hypothesis that nicorandil has anti-apoptotic effects in endothelial cells (ECs). Apoptosis was induced by serum starvation in the culture media in human umbilical vein endothelial cells. We examined the effects of nicorandil on endothelial cell apoptosis. Cell viability after serum starvation was significantly higher in the nicorandil-treated group compared with the control group (81 +/- 8% vs. 63 +/- 3%, P < 0.01). Apoptosis, as detected by caspase 3 activation and Hoechst 33258 assay, induced by serum starvation was also effectively abrogated by the treatment of nicorandil (100 muM). The protective effects of nicorandil on endothelial survival were significantly inhibited by a specific mitochondrial KATP channel blocker, 5-Hydroxydecanoic acid. A mitochondrial permeability transition pore activator significantly abolished the anti-apoptotic effect of nicorandil in endothelial cells, indicating that the mechanism of protective effect of nicorandil is involved in the mitochondrial apoptotic pathway although it affects neither Bcl-2 nor Bax protein expression levels. In conclusion, nicorandil inhibits serum starvation-induced endothelial cell apoptosis possibly through mitochondrial KATP channels.
J Cardiovasc Pharmacol 2005 Dec
PMID:Nicorandil inhibits serum starvation-induced apoptosis in vascular endothelial cells. 1630 93

We sought to determine the relative myotoxicity of a sample of cardiotonic (catecholaminergic and PDE Inhibitory) agents currently available for clinical use. Male Wistar rats (292 +/- 24 g) were administered single subcutaneous injections of 20 mmol kg(-1) of each agent. Myocyte apoptosis (caspase-3 and annexin-V) and necrosis (anti-myosin antibody) were detected immunohistochemically on cryosections of the heart and soleus muscle. All of the cardiotonic agents except dopamine produced significant amounts of cardiomyocyte death compared with the vehicle controls, with necrosis (range 2-8%, p < 0.01) approximately one order of magnitude greater in extent than apoptosis (range 0.06-0.5%, p < 0.05). The incidence of necrosis induced by norepinephrine (8%) was approximately twice that of epinephrine and isoproterenol (4 %) and four times that of dobutamine and milrinone (2%). All agents were also toxic to the soleus muscle (range 0.1-8%), but isoproterenol (8%, p < 0.05) and epinephrine (4%, p < 0.05) were the most significant. No cell death was detected in control animals treated with only the vehicle. A majority of cardiotonic agents currently in clinical use are toxic to cardiac and skeletal myocytes. These observations suggest that judicious clinical use of such agents requires careful weighing of potential benefits against the harm via accelerated cumulative loss of myocytes.
Cardiovasc Toxicol 2005
PMID:Relative toxicity of cardiotonic agents: some induce more cardiac and skeletal myocyte apoptosis and necrosis in vivo than others. 1638 73

Doxorubicin (DOX), a potent antineoplastic agent, poses limitations for its therapeutic use due to the associated risk of developing cardiomyopathy and congestive heart failure. The cardiotoxicity of doxorubicin is associated with oxidative stress and apoptosis. We have recently shown that Spirulina, a blue-green alga with potent antioxidant properties, offered significant protection against doxorubicin-induced cardiotoxicity in mice. The aim of the present study was to establish the possible protective role of C-phycocyanin, one of the active ingredients of Spirulina, against doxorubicin-induced oxidative stress and apoptosis. The study was carried out using cardiomyocytes isolated from adult rat hearts. Doxorubicin significantly enhanced the formation of reactive oxygen species (ROS) in cells as measured by the 2',7'-dichlorodihydrofluorescein diacetate and dihydroethidium fluorescence. The doxorubicin-induced reactive oxygen species formation was significantly attenuated in cells pretreated with C-phycocyanin. It was further observed that the doxorubicin-induced DNA fragmentation and apoptosis, as assayed by TUNEL assay and flow cytometry coupled with BrdU-FITC/propidium iodide staining, were markedly attenuated by C-phycocyanin. C-phycocyanin also significantly attenuated the doxorubicin-induced increase in the expression of Bax protein, release of cytochrome c, and increase in the activity of caspase-3 in cells. In summary, C-phycocyanin ameliorated doxorubicin-induced oxidative stress and apoptosis in cardiomyocytes. This study further supports the crucial role of the antioxidant nature of C-phycocyanin in its cardioprotection against doxorubicin-induced oxidative stress and apoptosis.
J Cardiovasc Pharmacol 2006 Jan
PMID:C-phycocyanin ameliorates doxorubicin-induced oxidative stress and apoptosis in adult rat cardiomyocytes. 1642 80

The objective of this study was to characterize acute coronary artery injury evoked by the endothelin A receptor (ETAR) antagonist, CI-1034. Male dogs (n = 5) were intravenously administered CI-1034 at 120 mg/kg for 4 d. Control animals (n = 3) received vehicle. Macroscopically, drug-related hemorrhage was observed in the right coronary groove and atrium. Histologically, drugrelated coronary changes were characterized as medial hemorrhage and necrosis, with mixed inflammatory-cell infiltrates in the adventitia and media. Immunohistochemistry staining indicated increased expression of inducible nitric oxide synthase (iNOS), cleaved caspase-3, and S100A8/A9 (within in monocytes and neutrophils) proteins in coronary arteries of CI-1034-treated animals. However, there were similar expression levels of endothelial nitric oxide synthase (eNOS) among control and CI-1034-treated animals. Significant drug-related nitric oxide (NO) accumulation occurred on days 1 through 4 in serum. Increased interleukin (IL)-6 and fibrinogen in plasma and serum amyloid A (SAA) occurred on days 2 through 5 in CI-1034-treated animals. Increased levels of NO accumulation in serum; increased IL-6 and fibrinogen levels in plasma; increased SAA levels; and increased expressions of iNOS, cleaved caspase-3, and S100A8/A9 complex appear to be characteristic of CI-1034-induced acute vascular injury in dogs.
Cardiovasc Toxicol 2006
PMID:Acute coronary artery injury in dogs following administration of CI-1034, an endothelin A receptor antagonist. 1684 80

DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride-3.5 hydrate) inhibits Ca(2+)/CaM-dependent nitric oxide synthase (NOS), thereby inhibiting nitric oxide (NO) production. In cardiomyocytes from ischemic rat heart NO and superoxide levels are increased causing protein tyrosine nitration. In hearts subjected to ischemia/reperfusion DY-9760e totally abolishes protein tyrosine nitration. Notably, DY-9760e also inhibits calpain and cas-pase-3 activation that occurs prior to apoptosis in cardiomyocytes. In ischemic hearts fodrin is the substrate for calpain. DY-9760e inhibits fodrin breakdown in the peri-infarct area rather than in the infarct core. In the ischemic rat brain DY-9760e inhibits caspase-3-induced proteolysis of calpastatin, an endogenous calpain inhibitor, suggesting that crosstalk between calpain and caspase-3 is mediated by calpastatin breakdown. Thus, DY-9760e rescues neurons and cardiomyocytes from ischemic injury by inhibiting crosstalk between calpain and caspase-3 as well as protein tyrosine nitration.
Cardiovasc Drug Rev 2006
PMID:DY-9760e, a novel calmodulin inhibitor, exhibits cardioprotective effects in the ischemic heart. 1696 23


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