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)

Successful lung transplantation has been limited by the high incidence of acute graft rejection. There is mounting evidence that the stress response gene heme oxygenase-1 (HO-1) and/or its catalytic by-product carbon monoxide (CO) confers cytoprotection against tissue and cellular injury. This led us to hypothesize that CO may protect against lung transplant rejection via its anti-inflammatory and antiapoptotic effects. Orthotopic left lung transplantation was performed in Lewis rat recipients from Brown-Norway rat donors. HO-1 mRNA and protein expression were markedly induced in transplanted rat lungs compared to sham-operated control lungs. Transplanted lungs developed severe intraalveolar hemorrhage, marked infiltration of inflammatory cells, and intravascular coagulation. However, in the presence of CO exposure (500 ppm), the gross anatomy and histology of transplanted lungs showed marked preservation. Furthermore, transplanted lungs displayed increased apoptotic cell death compared with the transplanted lungs of CO-exposed recipients, as assessed by TUNEL and caspase-3 immunostaining. CO exposure inhibited the induction of IL-6 mRNA and protein expression in lung and serum, respectively. Gene array analysis revealed that CO also down-regulated other proinflammatory genes, including MIP-1alpha and MIF, and growth factors such as platelet-derived growth factor, which were up-regulated by transplantation. These data suggest that the anti-inflammatory and antiapoptotic properties of CO confer potent cytoprotection in a rat model of lung transplantation.
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PMID:Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via anti-inflammatory and anti-apoptotic effects. 1281 27

Apoptosis has been associated with several events in solid organ transplantation, including ischemia/reperfusion (IR) injury and acute rejection. To determine whether apoptosis-profiles may distinguish these two conditions, we analyzed apoptosis rates in a rat orthotopic small bowel transplant (SBT) model. SBT was performed in Lewis rats with either freshly harvested or preserved (4 h, in UW at 4 degrees C) syngeneic and allogeneic (Brown-Norway) grafts. Bowel samples were collected 2 h after reperfusion and on small bowel transplant postoperative days (POD) 1, 4, and 7. Apoptosis was detected by measuring levels of histone-associated DNA fragments and caspase 3 expression, and by determining apoptotic body counts. All markers measured 2 h after reperfusion increased profoundly in association with preservation. After a significant decrease on POD 1, apoptosis rates rose again between POD 4 and 7 only in allogeneic grafts. This distinct second increase in apoptosis may be an early and specific sign of acute rejection.
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PMID:Increased apoptosis is specific for acute rejection in rat small bowel transplant. 1512 82

Brown Norway (BN) and BN Katholiek (BN/Ka) rat strains are both susceptible to develop lesions in the internal elastic lamina (IEL) of the aorta. BN/Ka rats are characterized by a single point mutation in the kininogen gene leading to deficiency in high- and low-molecular-weight kininogen. Recently, a suggestive quantitative trait locus for lesions in the IEL of the abdominal aorta was identified in an F2 intercross between Dahl salt-sensitive (SS) and BN rats, implicating kininogen as a positional candidate gene. Therefore, BN and BN/Ka rat strains represent ideal model organisms with which to study the contribution of kininogen to the genetic predisposition to IEL lesion formation and to characterize the early events underlying vascular remodeling. Here we present data demonstrating that genetic kininogen deficiency promotes the formation of aneurysms in the abdominal aorta but not the development of atherosclerosis upon 12-wk treatment with an atherogenic diet. Aneurysm formation was associated with an enhanced elastolysis, increased expression of MMP-2 and MMP-3, downregulation of TIMP-4, and with FasL- and caspase-3-mediated apoptosis. Kininogen-deficient animals also featured changes in plasma cytokines compatible with apoptotic vascular damage, i.e., upregulation of IFN-gamma and downregulation of GM-CSF and IL-1beta. Finally, in response to atherogenic diet, kininogen-deficient animals developed an increase in HDL/total cholesterol index, pronounced fatty liver and heart degeneration, and lipid depositions in aortic media without atherosclerotic plaque formation. These findings suggest that genetic kininogen deficiency renders vascular tissue prone to aneurysmatic but not to atherosclerotic lesions.
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PMID:Genetic kininogen deficiency contributes to aortic aneurysm formation but not to atherosclerosis. 1523 17

Muscle atrophy is associated with a loss of muscle fiber nuclei, most likely through apoptosis. We investigated age-related differences in the extent of apoptosis in soleus muscle of young (6 mo) and old (32 mo) male Fischer 344 x Brown Norway rats subjected to acute disuse atrophy induced by 14 days of hindlimb suspension (HS). HS-induced atrophy (reduction in muscle weight and cross-sectional area) was associated with loss of myofiber nuclei in soleus muscle of young, but not old, rats. This resulted in a significant decrease in the myonuclear domain (cross-sectional area per nucleus) in young and old rats, with changes being more pronounced in old animals. Levels of apoptosis (TdT-mediated dUTP nick end labeling and DNA fragmentation) were higher in soleus muscles of old control rats than young animals. Levels were significantly increased with HS in young and old rats, with the greatest changes in old animals. Caspase-3 activity in soleus muscle tended to be increased with age, but changes were not statistically significant (P=0.052). However, with HS, caspase-3 activity significantly increased in young, but not old, rats. Immunohistochemistry showed that the proapoptotic endonuclease G (EndoG, a mitochondrion-specific nuclease) was localized in the subsarcolemmal mitochondria in control muscles, and translocation to the nucleus occurred in old, but not young, control animals. There was no difference between EndoG total protein content in young and old control rats, but EndoG increased almost fivefold in soleus muscle of old, but not young, rats after HS. These results show that deregulation of myonuclear number occurs in old skeletal muscle and that the pathways involved in apoptosis are distinct in young and old muscles. Apoptosis in skeletal muscle is partly mediated by the subsarcolemmal mitochondria through EndoG translocation to the nucleus in response to HS.
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PMID:Age-related differences in apoptosis with disuse atrophy in soleus muscle. 1565 Jan 25

Aging of skeletal muscle is often accompanied by muscle atrophy and it appears that apoptosis plays an important role in this process. The detailed mechanism(s) is not completely understood, however. In this study, we examined expression of the apoptosis regulatory proteins as well as the heat shock proteins, which have been shown to modulate the apoptotic process in certain cell types, in order to more completely elucidate apoptotic signaling in aged skeletal muscle. To more specifically identify alterations that are likely to be the result of aging, we compared 16-month-old middle-aged (MD) and 29-month-old senescent (SE) male Fischer 344 x Brown Norway rats in our study. Our results show that the degree of DNA laddering was higher in SE compared to MD rats. Using total tissue homogenates we examined the level of expression of several apoptosis-related proteins in two categories: mitochondria-associated proteins and caspases. Of the mitochondria-associated proteins, the levels of p53 showed a significant increase in SE compared to MD rats. There was also a significant increase in the expression of Bax, Bcl-2 and Apaf-1 in SE rats over that of MD rats; cytochrome c and AIF levels remained unchanged, however. Regarding the caspases, there were increases in the levels of pro-caspases-12 and -7 and cleaved caspase-9, although the levels of pro- and cleaved caspase-3 as well as cleaved caspase-12 remained unchanged. Furthermore, our results showed significant increases in HSP27, HSP60, and the inducible HSP70. These data show that in rat skeletal muscle increased apoptosis occurs between middle-age and senescence, indicating an aging-related increase in apoptosis in skeletal muscle. The involvement of different apoptotic pathways in the aging process is suggested by the selective alterations in the apoptosis regulatory proteins. The increased expression of the HSPs suggests a relationship between HSPs and the aging-related apoptotic process.
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PMID:Age-related alterations in expression of apoptosis regulatory proteins and heat shock proteins in rat skeletal muscle. 1613 96

Age-related decreases in muscle mass have been associated with the loss of myonuclei, possibly through a mechanism involving mitochondria. It is unclear if age-related apoptotic mechanisms vary by fiber type. Here we investigate indices of apoptosis along with the regulation of apoptotic mediators in the extensor digitorum longus (EDL) and soleus of adult (6 month), old (30 month), and very old (36 month) Fischer 344/NNiaHSD x Brown Norway/BiNia (F344/N x BN) rats. Compared to 6-month muscles, aged muscles exhibited decreases in muscle mass along with increases in the number of nuclei staining positively for DNA fragmentation. The expression of Bax, Bcl-2, caspase-3 and caspase-9 was regulated differently with aging between muscle types and in a manner not consistent with mitochondria-mediated apoptosis. To investigate the potential of calpain involvement in age-related myonuclear loss, the calpain-dependent cleavage of alpha-fodrin was examined. The proteolytic cleavage of alpha-fodrin by calpains was increased in both muscles with only the 36-month soleus exhibiting increased caspase-dependent alpha-fodrin cleavage. Taken together, these data suggest that apoptotic regulatory events differ between fiber types in the aging F344/N x BN and that mitochondrial-dependent apoptosis pathways may not play a primary role in the loss of muscle nuclei with aging.
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PMID:Sarcopenia-related apoptosis is regulated differently in fast- and slow-twitch muscles of the aging F344/N x BN rat model. 1667 39

Tumor necrosis factor-alpha (TNF-alpha) is elevated in the serum as a result of aging and it promotes pro-apoptotic signaling upon binding to the type I TNF receptor. It is not known if activation of this apoptotic pathway contributes to the well-documented age-associated decline in muscle mass (i.e. sarcopenia). We tested the hypothesis that skeletal muscles from aged rodents would exhibit elevations in markers involved in the extrinsic apoptotic pathway when compared to muscles from young adult rodents, thereby contributing to an increased incidence of nuclear apoptosis in these muscles. The plantaris (fast) and soleus (slow) muscles were studied in young adult (5-7 mo, n=8) and aged (33 mo, n=8) Fischer(344) x Brown Norway rats. Muscles from aged rats were significantly smaller while exhibiting a greater incidence of apoptosis. Furthermore, muscles from aged rats had higher type I TNF receptor and Fas associated death domain protein (FADD) mRNA, protein contents for FADD, BCL-2 Interacting Domain (Bid), FLICE-inhibitory protein (FLIP), and enzymatic activities of caspase-8 and caspase-3 than muscles from young adult rats. Significant correlations were observed in the plantaris muscle between caspase activity and muscle weight and the apoptotic index, while similar relationships were not found in the soleus. These data demonstrate that pro-apoptotic signaling downstream of the TNF receptor is active in aged muscles. Furthermore, our data extend the previous demonstration that type II fibers are preferentially affected by aging and support the hypothesis that type II fiber containing skeletal muscles may be more susceptible to muscle mass loses via the extrinsic apoptotic pathway.
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PMID:Death receptor-associated pro-apoptotic signaling in aged skeletal muscle. 1705 37

Growth hormone (GH) supplementation at old age has been shown to improve body composition, although its effect on muscle performance is still debated. On the other hand, resistance training increases muscle mass and strength even when initiated at advanced age. In the present study, we investigated the effects of short-term GH supplementation and exercise training on physical performance and skeletal muscle apoptosis in aged rats. Old (28 mo) male Fischer 344 x Brown Norway rats were randomized to 4 wk of GH supplementation (300 mug subcutaneous, twice daily) or 4 wk of treadmill running or used as sedentary controls. Eight-month-old rats, sedentary or exercised, were used as young controls. Exercise training improved exercise capacity and muscle strength in old animals. In soleus muscle, age and exercise were not associated with significant changes in the extent of apoptosis. However, we detected an age-related increase of cleaved caspase-8 (+98%), cleaved caspase-3 (+136%), and apoptotic DNA fragmentation (+203%) in the extensor digitorum longus muscle of old sedentary rats, which was attenuated by exercise. GH administration neither ameliorated physical performance nor attenuated apoptosis in extensor digitorum longus and was associated with increased apoptosis in soleus muscle (+206% vs. old controls). Our findings indicate that a short-term program of exercise training started at advanced age reverses age-related skeletal muscle apoptosis and represents an effective strategy to improve physical performance. In contrast, short-term administration of GH late in life does not provide any protection against functional decline or muscle aging and may even accelerate apoptosis in slow-twitch muscles, such as the soleus.
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PMID:Effects of short-term GH supplementation and treadmill exercise training on physical performance and skeletal muscle apoptosis in old rats. 1800 94

Tissue kallikrein exerts various biological functions through kinin formation with subsequent kinin B2 receptor activation. Recent studies showed that tissue kallikrein directly activates kinin B2 receptor in cultured cells expressing human kinin B2 receptor. In the present study, we investigated the role of tissue kallikrein in protection against cardiac injury through direct kinin B2 receptor activation using kininogen-deficient Brown Norway Katholiek rats after acute myocardial infarction. Tissue kallikrein was injected locally into the myocardium of Brown Norway Katholiek rats after coronary artery ligation with and without coinjection of icatibant (a kinin B2 receptor antagonist) and N(omega)-nitro-L-arginine methylester (an NO synthase inhibitor). One day after myocardial infarction, tissue kallikrein treatment significantly improved cardiac contractility and reduced myocardial infarct size and left ventricle end diastolic pressure in Brown Norway Katholiek rats. Kallikrein attenuated ischemia-induced apoptosis and monocyte/macrophage accumulation in the ischemic myocardium in conjunction with increased NO levels and reduced myeloperoxidase activity. Icatibant and N(omega)-nitro-L-arginine methylester abolished kallikrein's effects, indicating a kinin B2 receptor NO-mediated event. Moreover, inactive kallikrein had no beneficial effects in cardiac function, myocardial infarction, apoptosis, or inflammatory cell infiltration after myocardial infarction. In primary cardiomyocytes derived from Brown Norway Katholiek rats under serum-free conditions, active, but not inactive, kallikrein reduced hypoxia/reoxygenation-induced apoptosis and caspase-3 activity, and the effects were mediated by kinin B2 receptor/nitric oxide formation. This is the first study to demonstrate that tissue kallikrein directly activates kinin B2 receptor in the absence of kininogen to reduce infarct size, apoptosis, and inflammation and improve cardiac performance of infarcted hearts.
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PMID:Tissue kallikrein elicits cardioprotection by direct kinin b2 receptor activation independent of kinin formation. 1876

Changes in the structure and function of aging non-locomotor muscles remains understudied, despite their importance for daily living. Extraocular muscles (EOMs) have a high incidence of age-related mitochondrial defects possibly because of the metabolic stress resulting from their fast and constant activity. Apoptosis and autophagy (type I and II cell death, respectively) are linked to defects in mitochondrial function and contribute to sarcopenia in hind limb muscles. Therefore, we hypothesized that apoptosis and autophagy are altered with age in the EOMs. Muscles from 6-, 18-, and 30-month-old male Fisher 344-Brown Norway rats were used to investigate type I cell death, caspase-3, -8, -9, and -12 activity, and type II cell death. Apoptosis, as measured by TUNEL positive nuclei, and mono- and oligo-nucleosomal content, did not change with age. Similarly, caspase-3, -8, -9, and -12 activity was not affected by aging. By contrast, autophagy, as estimated by gene expression of Atg5 and Atg7, and protein abundance of LC3 was lower in EOMs of aged rats. Based on these data, we suggest that the decrease in autophagy with age leads to the accumulation of damaged organelles, particularly mitochondria, which results in the decrease in function observed in EOM with age.
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PMID:Age-related changes of cell death pathways in rat extraocular muscle. 1934 88


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