Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NCO-700 is a newly synthesized inhibitor of both cathepsin B and calcium-activated neutral protease. We examined whether NCO-700 inhibits degradation of myofibrillar proteins induced by cardiac ischemia in dogs anesthetized with pentobarbital. Cardiac ischemia was produced by complete occlusion of the left anterior descending coronary artery (LAD) for 3 or 6 hr. Myofibrils were prepared from the ischemic myocardium, in which LAD was occluded, and from the nonischemic myocardium, in which LAD was not occluded. Electrophoresis of myofibrils prepared from the ischemic myocardium revealed that there were many degradation bands of myofibrillar proteins as well as the bands corresponding to alpha-actinin (AN), the 55 kDa protein (55 K), actin (A), tropomyosin (TM), troponin I (TN I), myosin light chain 1 (LC1) and myosin light chain 2 (LC2). In addition, the content of AN, 55 K, A, TM, TN I, LC1 and LC2 in the ischemic myofibrils was lower than that in the nonischemic myofibrils. Treatment with NCO-700 at the total dose of 20 mg/kg, which was injected intravenously before and during ischemia, inhibited both appearance of the degradation bands and the decrease in the content of A, TM, TN I, LC1 and LC2 being produced by cardiac ischemia. NCO-700, however, did not inhibit the decrease in the content of 55K and AN being induced by ischemia.
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PMID:Inhibition with NCO-700, a protease inhibitor, of degradation of cardiac myofibrillar proteins during ischemia in dogs. 406 61

Previous studies on cytoskeletal changes of in vitro and in vivo animal models of ischemic myocardium have suggested the possibility of using alterations in cytoskeleton proteins as an early marker for the post-mortem diagnosis of myocardial ischemia in cases of sudden death due to coronary artery disease (CAD). In the present study, using the technique of ABC-immunohistochemistry, we examine the changes of three cytoskeletal proteins: vinculin, desmin and alpha-actinin in human myocardial samples taken from 14 cases of CAD sudden death and 13 cases of non-CAD death. Results of these examinations are compared with immunohistochemical changes of myoglobin and histochemical staining of hematoxylin and eosin and phosphotungstic acid, and Masson trichrome. Patchy and extensive loss of the three cytoskeletal proteins was demonstrated in the myocardium of victims who died 1 h or later following the onset of symptoms of ischemic myocardium. The pattern of cytoskeleton change is equivocal in the cases of CAD who died less than 1 h after the onset of symptoms and of the cases of non-CAD. In these cases, no significant histological change was observed. With less non-specific background changes and stronger positive staining, immunohistochemical staining of the three cytoskeletal proteins is more reliable than myoglobin, which has attracted the attention of many pathologists searching for anatomic evidence of ischemic myocardium in coronary artery disease.
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PMID:Cytoskeleton immunohistochemical study of early ischemic myocardium. 868 23

The presence of cardiac proteins in serum has been related to ischemic heart diseases such as acute myocardial infarction and angina pectoris, which are more frequent in non-insulin-dependent diabetic patients. Silent myocardial ischemia, which is also more frequent in these patients, occurs in association with autonomic dysfunction. We used Western blot analysis to search the myocardial protein alpha-actinin in sera from non-insulin-dependent diabetic patients with or without autonomic dysfunction. Of the 24 diabetic patients with neuropathy, 18 were positive for circulating alpha-actinin; this protein was found in only 1 of the 22 diabetic patients without neuropathy. Our results showed a significant correlation between non-insulin-dependent diabetic patients with neuropathy and detectable circulating alpha-actinin in serum, and suggest that the determination by immunoblotting of serum alpha-actinin in these patients may be an effective method to detect myocardial cell impairment, and to identify diabetic patients that may need special consideration.
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PMID:Detection of circulating alpha-actinin in non-insulin-dependent diabetics with autonomic dysfunction. 879 60

Cardiomyocyte apoptosis is present in many cardiac disease states, including heart failure and ischemic heart disease. Apoptosis is associated with the activation of caspases that mediate the cleavage of vital and structural proteins. However, the functional contribution of apoptosis to these conditions is not known. Furthermore, in cardiac myocytes, apoptosis may not be complete, allowing the cells to persist for a prolonged period within the myocardium. Therefore, we examined whether caspase-3 cleaved cardiac myofibrillar proteins and, if so, whether it affects contractile function. The effects of caspase-3 were studied in vitro on individual components of the cardiac myofilament including alpha-actin, alpha-actinin, myosin heavy chain, myosin light chain 1/2, tropomyosin, cardiac troponins (T, I, C), and the trimeric troponin complex. Exposure of the myofibrillar protein (listed above) to caspase-3 for 4 h resulted in the cleavage of alpha-actin and alpha-actinin, but not myosin heavy chain, myosin light chain 1/2, and tropomyosin, into three fragments (30, 20, and 15 kDa) and one major fragment (45 kDa), respectively. When cTnT, cTnI, and cTnC were incubated individually with caspase-3, there was no detectable cleavage. However, when the recombinant troponin complex was exposed to caspase-3, cTnT was cleaved, resulting in fragments of 25 kDa. Furthermore, rat cardiac myofilaments exposed to caspase-3 exhibited similar patterns of myofibrillar protein cleavage. Treatment with the caspase inhibitor DEVD-CHO or z-VAD-fmk abolished the cleavage. Myofilaments, isolated from adult rat ventricular myocytes after induction of apoptotic pathway by using beta-adrenergic stimulation, displayed a similar pattern of actin and TnT cleavage. Exposure of skinned fiber to caspase-3 decreased maximal Ca(2+)-activated force and myofibrillar ATPase activity. Our results indicate that caspase-3 cleaved myofibrillar proteins, resulting in an impaired force/Ca(2+) relationship and myofibrillar ATPase activity. Induction of apoptosis in cardiac cells was associated with similar cleavage of myofilaments. Therefore, activation of apoptotic pathways may lead to contractile dysfunction before cell death.
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PMID:Functional consequences of caspase activation in cardiac myocytes. 1197 44

Matrix metalloproteinase (MMP)-2 mediates myocardial ischemia-reperfusion injury which is characterized by enhanced peroxynitrite biosynthesis during early reperfusion. Direct infusion of peroxynitrite into isolated hearts activates MMP-2 prior to the loss in mechanical function. The mechanical dysfunction is prevented by MMPs inhibitors. MMP-2 is also found in the sarcomere of cardiomyocytes where it cleaves troponin I and myosin light chain I. Cytoskeletal proteins such as alpha-actinin, desmin and spectrin are found in close association with the sarcomere and are known to be degraded in ischemia-reperfusion injury. It remains unknown whether these proteins are degraded in peroxynitrite-induced myocardial injury and if cytoskeletal proteins are also targets for MMP-2. Peroxynitrite (80 microM) was infused into isolated rat hearts which led to a delayed onset but rapidly developing decline in mechanical function. The MMPs inhibitor PD-166793 or the peroxynitrite scavenger glutathione prevented the decline in cardiac function. At the end of perfusion, alpha-actinin levels were decreased by 45+/-3% in peroxynitrite-infused hearts as compared to control hearts; however, this was normalized to that of control hearts with either PD-166793 or glutathione. Cardiac desmin and alphaII spectrin levels were unaltered following peroxynitrite infusion. alpha-Actinin and to a lesser extent desmin are susceptible to in vitro proteolysis by MMP-2 whereas spectrin is resistant. Cardiac dysfunction induced by peroxynitrite involves degradation of alpha-actinin that may be mediated by the proteolytic action of MMP-2.
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PMID:Matrix metalloproteinase-2 degrades the cytoskeletal protein alpha-actinin in peroxynitrite mediated myocardial injury. 1785 26

Bone marrow stromal cells (BMSC) can differentiate into various cell types including myocytes, which may be valuable in cellular therapy of myocardial infarction. In an attempt to increase the myogenic commitment of BMSC, we investigated the extent of conversion induced by the demethylation agent 5-azacytidine. BMSC isolated from the adult rat tibia were exposed in culture to 5microM 5-azacytidine for 24h, 1 day after seeding. The treatment was repeated at weekly intervals and the expression of muscle-specific proteins and genes was assessed. The results revealed that cultured cells lost the native expression of osteocalcin and alkaline phosphatase as a function of time and began to express connexin 43. Exposure to 5-azacytidine of BMSC induced, at 14 days, a myocyte-resembling phenotype that included the expression of muscle-specific proteins (sarcomeric alpha-actin, troponin T, desmin, alpha-actinin, and GATA-4) and genes (GATA-4, myoD, desmin, and alpha-actinin), numerous mitochondria and myofilaments; however, the latter did not form sarcomeres. Although some of these myogenic markers also appeared in untreated cells, exposure to 5-azacytidine induced an enhanced response of calcium channels, as well as a threefold increase in desmin and myoD gene expression and a twofold increase in alpha-actinin gene and protein expression above the control values. In conclusion, the results demonstrate a promoting effect of 5-azacytidine on the expression of muscle-specific proteins and genes in BMSC in culture. Notably, the myogenic differentiation takes place over a short period of time. Priming of mesenchymal cells to cardiomyogenic differentiation may have significant applications in cellular approaches to ameliorate muscle loss after myocardial ischemia.
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PMID:Promoting effect of 5-azacytidine on the myogenic differentiation of bone marrow stromal cells. 1803 91