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)

The release of cardioactive substances during hepatic ischemia/reperfusion injury generates toxic free radicals that inflict hepatic and remote cardiac damage. The aim of the study was to determine whether TPEN, a potent iron chelator, ameliorates the apoptotic hepatic and cardiac function injuries. Three groups of isolated rat livers were studied: (1) continuously perfused with Krebs-Henseleit solution; (2) subjected to 120 min of ischemia and 15 min of reperfusion; (3) as in group 2, with TPEN administered prior to ischemia. Isolated hearts were perfused for 65 min with the effluent of the reperfused livers. Results showed that TPEN administration reduced the release of norepinephrine, epinephrine, dopamine, prostaglandin E2 and angiotensin II, decreased intrahepatic caspase-3 activity, and decreased the mean hepatocyte apoptotic index (TUNEL assay) (p = 0.001). Perfusion with post-ischemic hepatic effluent caused a transient 15-min increase in left ventricular contraction and coronary flow (p < 0.05), followed by a decrease in cardiac function at one hour. TPEN reduced the transient elevation in left ventricular contraction p < 0.05), but did not prevent the subsequent decrease in cardiac function. In conclusion, TPEN attenuates post-ischemic apoptotic hepatic injury by modulating caspase-3-like activity and reduces the cardioactive substances released from the liver.
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PMID:TPEN attenuates hepatic apoptotic ischemia/ reperfusion injury and remote early cardiac dysfunction. 1571 22

Nitric oxide (NO) has been shown to play a key role in the regulation of cardiac hypertrophy and fibrosis in response to myocardial ischemia in part by antagonizing the action of angiotensin II (Ang II). In this study, we investigated the potential protective role of human endothelial nitric oxide synthase (eNOS) in left ventricular (LV) remodeling after myocardial infarction (MI) by a somatic gene transfer approach. Male Wistar rats underwent coronary artery ligation to induce MI. One week after surgery, adenovirus encoding the human eNOS or luciferase gene under the control of the CMV promoter/enhancer was injected into rats via the tail vein, and animals were sacrificed at 1 and 5 weeks after gene transfer. Successful gene transfer was evaluated based on increased levels of NO and cGMP in the heart, measured at one week after eNOS gene delivery. Six weeks after MI, the LV end-diastolic pressure, heart weight, LV axis length and cardiomyocyte size were markedly increased compared to the Sham group, while eNOS gene delivery significantly reduced these parameters. Rats receiving control virus developed considerably more fibrotic lesions identified by Sirius Red staining and collagen I immunostaining compared to Sham rats, and eNOS gene delivery significantly reduced collagen accumulation. eNOS gene transfer also reduced TUNEL-positive apoptotic cells. The cardioprotective effect of NO was accompanied by reduced NADH and NADPH oxidase activities and superoxide formation, TGF-beta1 and p27 levels, JNK activation, NF-kappa B nuclear translocation, and caspase-3 activity. This study shows that NO may play an important role in attenuating cardiac remodeling and apoptosis after myocardial infarction via suppression of oxidative stress-mediated signaling pathways.
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PMID:Human endothelial nitric oxide synthase gene delivery protects against cardiac remodeling and reduces oxidative stress after myocardial infarction. 1576 77

Our previous work has established that angiotensin II is cardiotoxic. Here we sought to investigate whether skeletal muscle is similarly susceptible to damage. Male Wistar rats were either given a single subcutaneous injection of angiotensin II (range 1 microg kg-1 to 10 mg kg-1) or only the vehicle and killed 7 h later, or implanted with preconditioned osmotic pumps dispensing 1 mg kg-1 day-1 angiotensin II and killed 9 or 18 h later. Apoptotic (caspase 3 positive) myocytes were counted on cryosections of the heart, soleus, tibialis anterior and diaphragm muscle. Single injections of 100 microg kg-1 to 10 mg kg-1 angiotensin II induced significant (P<0.05) myocyte apoptosis (per 10(4) viable myocytes) in the heart and this was heterogeneously distributed, peaking (5.7+/-0.6; P<0.05) at a point 6 mm from the apex, i.e. approximately three-quarters of the way towards the base. The slow-twitch soleus muscle was also damaged significantly (peak=2.6+/-0.4; P<0.05), while only the administration of 1 mg kg-1 induced significant (P<0.05) apoptosis in the fast-twitch tibialis anterior muscle (peak=1.2+/-0.3). Infusion of 1 mg kg-1 day-1 angiotensin II induced more myocyte apoptosis than a single bolus administration of the same dose, and in general there was a higher incidence of apoptosis in muscles harvested after 18 than after 9 h. Infusion of 1 mg kg-1 day-1 angiotensin II over 18 h induced significant (P<0.05) myocyte apoptosis in the heart (3.3+/-0.4), soleus (3.9+/-1), tibialis anterior (5.9+/-0.4) and diaphragm (19.8+/-5.6) muscle. Depending on the muscle type, angiotensin II induces myocyte apoptosis in skeletal muscle to a similar or greater extent as in cardiac muscle, supporting the hypothesis that angiotensin II is generally toxic to all striated muscles.
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PMID:Angiotensin II induces apoptosis in vivo in skeletal, as well as cardiac, muscle of the rat. 1598 33

Arterial hypertension is a leading contributor to the progression of chronic renal disease. Short-term studies had addressed the role of oxidative stress in hypertensive nephropathy. We have now studied oxidative stress and caspase activation in a long-term model of hypertensive renal injury. Nontreated spontaneously hypertensive rats with uninephrectomy displayed severe arterial hypertension over a 36-week follow-up. Uncontrolled high blood pressure in the context of modest renal mass reduction resulted in significant histological renal injury. Blood pressure control by the angiotensin-converting enzyme (ACE) inhibitor, quinapril, or the AT1 receptor antagonist, losartan, decreased the degree of renal injury. Hypertensive renal injury was associated with evidence of activation of the apoptotic pathway (increased activation of caspase-3) and local renal (increased staining for 4-hydroxy-2-nonenal) and systemic [increased serum levels of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha)] lipid oxidation when compared with normotensive control rats. In addition, severe hypertension decreased the renal antioxidant defenses, as exemplified by decreased expression of Cu/Zn superoxide dismutase. Treatment with quinapril or losartan decreased caspase-3 activation, 4-hydroxy-2-nonenal staining, and 8-iso-PGF2alpha levels and increased Cu/Zn superoxide dismutase expression. These results suggest that hypertension-associated oxidative stress and its consequences may be decreased by either ACE inhibition or AT1 receptor antagonist, emphasizing the role of angiotensin II in hypertensive renal damage.
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PMID:Long-term blood pressure control prevents oxidative renal injury. 1611 34

Angiotensin II stimulates NADPH oxidase activity in vascular cells. However, it is not fully understood whether angiotensin II, which plays an important role in heart failure, stimulates NADPH oxidase activation and expression in cardiac myocytes. Previous studies have shown that angiotensin II induces myocyte apoptosis, but whether the change is mediated via NADPH oxidase remains to be elucidated. In this study we proposed to determine whether angiotensin II stimulated NADPH oxidase activation and NADPH oxidase subunit p47-phox expression in H9C2 cardiac muscle cells. If so, we would determine whether the NADPH oxidase inhibitor apocynin prevented angiotensin II-induced apoptosis. The results showed that angiotensin II increased NADPH oxidase activity, p47-phox protein and mRNA expression, intracellular reactive oxygen species, and apoptosis in H9C2 cells. Angiotensin II elevated p38 mitogen-activated protein kinase (MAPK) activity, decreased Bcl-2 protein, and increased Bax protein and caspase-3 activity. Apocynin treatment inhibited angiotensin II-induced NADPH oxidase activation and increases in p47-phox expression, intracellular reactive oxygen species, and apoptosis. The effect of apocynin on apoptosis was associated with reduced p38 MAPK activity, increased Bcl-2 protein, and decreased Bax protein and caspase-3 activity. These results suggest that angiotensin II-induced apoptosis is mediated via NADPH oxidase activation probably through p38 MAPK activation, a decrease in Bcl-2 protein, and caspase activation.
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PMID:NADPH oxidase is involved in angiotensin II-induced apoptosis in H9C2 cardiac muscle cells: effects of apocynin. 1641 6

Cardiomyocyte apoptosis leads to the functional incapacitation of myocardial plasmodium and plays an important role in the pathogenesis of heart failure transformed from compensable cardiac hypertrophy. Mitochondria are the main source of apoptosis-inducing molecule of various cells, and the role of caspartate-specific cysteinyl proteinase (caspase)-dependent mechanism has generally been accepted in the cardiomyocyte apoptosis. However, the significance of caspase-independent apoptosis-inducing factor (AIF) mechanism is not yet understood. The purpose of this study was to evaluate hypoxia-reperfusion-induced alterations of AIF mRNA and protein expressions in hypertrophic cardiomyocytes. Cardiomyocyte hypertrophy was produced by angiotensin II (0.1 mumol/L). The cells were cultured under the condition of hypoxia (95% N2 and 5% CO2; the O2 partial pressure was lower than 5 mmHg) for 8 h or 12 h (named as H8h and H12h groups, respectively), and then exposed to normal culture environment (named as H8h/R and H12h/R groups, respectively). Apoptosis was detected with Hoechst 33258 staining. The AIF mRNA and protein expressions were detected by RT-PCR and Western blot and quantified by gel scanning. The results were as follows: (1) The level of AIF mRNA expression was 0.29+/-0.08 (optical density, relative value) in the control group (hypertrophic cardiomyocytes cultured in normal environment). Compared with that in the control group, the levels of AIF mRNA expression were significantly higher in the groups of H8h and H12h (0.52+/-0.04 and 0.85+/-0.10), indicating that this effect was time-dependent. A further increase of AIF mRNA expression was observed in the groups of H8h/R (1.09+/-0.12) and H12h/R (1.41+/-0.23). (2) The level of AIF protein expression was 0.29+/-0.04 in the control group. Compared with that in the control group, the levels of AIF protein expression were significantly higher in the groups of H8h and H12h (2.07+/-0.15 and 3.12+/-0.19). The AIF protein expression was increased further in the groups of H8h/R (4.57+/-0.25) and H12h/R (5.71+/-0.27). The nuclear translocation of AIF protein was obvious only in the groups of H8h/R and H12h/R. (3) The expressions of AIF mRNA and protein were almost completely inhibited by AIF siRNA transfection. The siRNA transfection also reduced the apoptosis of hypertrophic cardiomyocytes in the groups of H8h/R and H12h/R but not in the groups of H8h and H12h. The apoptosis rate was significantly reduced by both AIF siRNA transfection and Ac-DEVD-cmk, an inhibitor of caspase-3. This reduction induced by two factors was more evident than that by one factor. (4) AIF nuclear translocation induced by hypoxia-reperfusion was not affected by inhibition of the activity of caspase-3. These data suggest that AIF plays a pivotal role in the apoptosis of hypertrophic cardiomyocytes induced by hypoxia-reperfusion.
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PMID:[Apoptosis of hypertrophic cardiomyocytes stimulated by hypoxia-reoxygenation is partially mediated by apoptosis-inducing factor]. 1717 96

Blockade of angiotensin II type 1 receptor (AT1) signaling attenuates heart failure following myocardial infarction (MI), perhaps through reduction of fibrosis in the noninfarcted myocardium. However, its specific effect on the infarct tissue itself has not been fully clarified, which we examined in the present study. After MI induction in mice, treatment with the AT1 blocker olmesartan, beginning on the 3rd day post-MI, significantly improved survival (94%) 4 wk post-MI, compared with saline (53%) and hydralazine (73%). Olmesartan-treated mice also showed significant attenuation of left ventricular dilatation and dysfunction, as well as significantly greater infarct wall thickness, although the absolute size of the infarct scar was unchanged. In addition, significantly greater numbers of nonmyocytes (mainly vascular cells and myofibroblasts) were present within the infarct scar in olmesartan-treated hearts. Ten days post-MI, apoptosis among granulation tissue cells was significantly suppressed in the olmesartan-treated hearts, where expression of Fas, Bax, procaspase-3, and Daxx and activation of caspase-3, c-Jun NH(2)-terminal kinase, and c-Jun were all significantly attenuated. By contrast, expression of Fas ligand, Bcl-2, and Fas-associated death domain and activation of caspase-8 were unaffected, suggesting olmesartan exerts a negative regulatory effect on the alternate pathway downstream of Fas receptor. In vitro, olmesartan dose-dependently inhibited Fas-mediated apoptosis in granulation tissue-derived myofibroblasts. The present study proposes this antiapoptotic effect as another important mechanism for an AT1 blocker in improving post-MI ventricular remodeling, as well as its antifibrotic effect, and also suggests a significant link between renin-angiotensin and Fas/Fas ligand systems in postinfarction hearts.
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PMID:Inhibition of Fas-associated apoptosis in granulation tissue cells accompanies attenuation of postinfarction left ventricular remodeling by olmesartan. 1720 88

We investigated the effects of castration and androgen administration on angiotensin II receptor mRNA expression and apoptosis related proteins in the rat bladders. Sprague-Dawley rats were divided into three groups: the control group (sham operation; n = 8), the castration group (castrated, 8 weeks old, n = 8) and the castration plus testosterone group (1% testosterone gel administrated percutaneously into the dorsum daily for 8 weeks starting at 4 weeks after castration, n = 8). Bladder total RNA was extracted, and real-time PCR was performed to quantitatively measure the mRNA expression of angiotensin converting enzyme (ACE), angiotensin II (A II) receptor type 1 (AT1 receptor) and A II receptor type II (AT2 receptor). Western blotting was performed to determine the expression of apoptosis-related proteins. Expression of AT2 receptor mRNA and caspase-3 protein significantly increased in the rat bladder after castration, and these increases were reduced to control levels by testosterone administration. These results suggest that expression of AT2 receptor and caspase-3 in the bladder is androgen-dependent. Expression of Bcl-2 and Bax protein in the rat bladder was not altered by castration. Expression of mitogen-activated protein (MAP) kinase phosphatase-1 protein in the rat urinary bladder was significantly increased by castration, but this increase was smaller with testosterone administration. These results suggest that expression of AT2 receptor mRNA and apoptosis-related proteins in the rat urinary bladder are affected by the change of androgen environment. The present study was the first to clarify the relationship between AT2 receptor and androgen in the urinary bladder.
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PMID:Effects of castration and testosterone administration on angiotensin II receptor mRNA expression and apoptosis-related proteins in rat urinary bladder. 1723 11

The cellular stress response can mediate cellular protection through expression of heat shock protein (Hsp70), which can interfere with the process of apoptotic cell death. Factors regulating renal epithelial cell apoptosis include angiotensin II. In the present study, we have examined the relationship between the Hsp70 expression and the apoptotic pathway in the kidneys from low-protein-fed rats (8% protein). The possible cytoprotective role of Hsp70 has been evaluated during low-protein feeding and after reincorporation of 24% protein in the diet. The effect of angiotensin II AT1 receptor inhibition has also been studied. Rats were fed with a low-protein (LP) diet (8% protein) for 14 days, and then the animals were recovered by means of a normal protein diet (24% protein) (RP) for 14, 21, and 30 days, and control rats received 24% protein (NP) in the diet. LP and NP rats treated with Losartan (10 mg/kg) were also evaluated. The following methods were performed on the kidneys: terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay for apoptosis, reverse transcriptase-polymerase chain reaction assay for AT1, Bax, and Bcl-2 messenger ribonucleic acid (mRNA) expression, and immunohistochemical and Western blot for Hsp70 and caspase 3 protein expression and activity. In the LP group, the cells of the medullary ducts (MDs) showed increased apoptosis associated with weak immunoreaction for Hsp70 and decreased Hsp70 protein levels. In these animals, enhanced proapoptotic ratio Bax/Bcl-2 linked to decreased procaspase 3 protein levels with increased caspase 3 activation were demonstrated. A cytoprotection attributed to Hsp70 could be noted in the RP rats after 21 days of reincorporation of the normal diet, and in the LP-fed group treated with Losartan. In these cases, the MD cells displayed decreased apoptosis and increased Hsp70 expression in colocalization staining, and high Hsp70 levels in cytosolic fraction. A decreased proapoptotic ratio Bax/Bcl-2, associated with increased Bcl-2 mRNA, was also observed. Our results provide evidence for an antiapoptotic, cytoprotective effect of Hsp70 in kidney MD cells of rats with LP intake, when the animals were recovered with 24% protein in diet and after angiotensin II AT1 receptor inhibition. Angiotensin II seems to play a role in the pathogenesis of tubule epithelial cell apoptosis during LP feeding.
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PMID:Heat shock protein 70 expression is associated with inhibition of renal tubule epithelial cell apoptosis during recovery from low-protein feeding. 1727 80

Obstruction-induced fibrosis is a leading cause of end-stage renal failure in children. The pathophysiological mechanisms may involve apoptosis and the renin-angiotensin system. We studied apoptosis and fibrosis in a well-established neonatal pig model with unilateral partial ureteral obstruction (PUUO) induced during ongoing nephrogenesis in 2-day-old piglets. The role of angiotensin II (ANG II) was studied using the AT(1) receptor blocker CV-11974 (0.12 mg/h candesartan from age 23 to 30 days). At day 30 the kidneys were perfusion fixed and fibrosis, apoptosis, and tubular lengths were quantitated using stereological methods, picro Sirius red staining, and immunohistochemical techniques identifying activated caspase 3, aquaporin-2 (AQP2), and von Willebrand factor. The collagen content was assessed by hydroxyproline density. Neonatal induced PUUO increased interstitial and glomerular cell apoptosis and fibrosis. At this stage, PUUO did not increase tubular cell apoptosis or decrease tubular length and cell number. AT(1) receptor blockade prevented the PUUO-induced interstitial and glomerular cell apoptosis but did not attenuate fibrosis. In conclusion, AT(1) receptor blockade after the end of nephrogenesis may prevent interstitial and glomerular cell apoptosis but not fibrosis, suggesting that pathways not involving AT(1) receptor stimulation contribute to neonatal obstruction-induced fibrosis or that prevention of interstitial cell apoptosis counteracts a potential antifibrotic effect of AT(1) receptor blockade in this pig model of congenital obstructive nephropathy. Our results demonstrate that ANG II plays a role in PUUO-induced glomerular cell apoptosis.
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PMID:AT1 receptor blockade prevents interstitial and glomerular apoptosis but not fibrosis in pigs with neonatal induced partial unilateral ureteral obstruction. 1735 26


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