Gene/Protein Disease Symptom Drug Enzyme Compound
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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

Ischemia is known to produce damage to subcellular organelles, such as nuclei and mitochondria, in myocardial tissue. We tested the hypothesis that during myocardial ischemia various cytoskeletal and contractile proteins also undergo changes. We induced total global ischemia by incubation in buffer of tissue samples from six human left ventricles that were obtained from heart transplant recipients. Samples were removed from the incubation medium at different time intervals and investigated by immunohistochemistry using monoclonal antibodies against myosin, actin, tropomyosin, troponin T, myomesin, desmin, tubulin, and vinculin. The degree of ischemic injury was determined by electron microscopy. Ischemic cardiomyopathic human tissue showed disturbances of the localization pattern of myosin, actin, tropomyosin, and troponin T as early as 10 minutes after the onset of ischemia; this disruption was complete at 20 minutes. Tubulin also started changing at 10 minutes, but complete disruption was only evident after 120 minutes. Desmin and myomesin showed an intermediate response; changes began at 30 to 40 minutes, and disruption was complete at 90 to 120 minutes. Vinculin was most resistant to ischemia. Ultrastructurally, the tissue showed moderate reversible ischemic injury during the entire period of 180 minutes. Measuring the exposure time in seconds allowed quantitation of the intensity of the fluorescence. We reached the following conclusions: (1) Ischemia causes damage to the contractile proteins sooner than to the cytoskeleton and subcellular organelles. (2) Diseased human hearts are extremely susceptible to the effects of ischemia. These findings are important for the situation of induced cardiac arrest in heart operations and for preservation of donor hearts for transplantation.
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PMID:Ischemia induces early changes to cytoskeletal and contractile proteins in diseased human myocardium. 760 73

An indirect ELISA method has been used to study formation of autoantibodies (AA) to myocardial myofibrillar proteins in patients with different clinical IHD forms. Purified myosin (MS), actin (AC) and tropomyosin (TM) of the intact human myocardium acted as antigens. The highest level of AA to MS and AC was found in patients with AMI (acute myocardial infarct): it exceeded twice that of the norm and 1.5 times that in patients with IAP (instable angina pectoris). Moreover the AA level in IAP patients exceeded that of normal 1.5 times. In PC (postinfactional cardiosclerosis) patients the MS AA and AC AA tend to the norm. The TM AA contents in PC patients is 1.2 times higher than that in AMI and IAP patients, not differing from the norm in all patient groups. The role of autosensibilization to contrectile proteins in progress of IHD and development of AMI is discussed.
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PMID:[Autosensitization to myofibrillar proteins of myocardium in patients with different clinical forms of ischemic heart disease]. 775 96

Tropomyosin is one of the key proteins for muscle contraction. We developed an enzyme-linked immunosorbent assay for antibodies to porcine muscle tropomyosin and measured serum anti-tropomyosin antibodies in patients with heart diseases and in normal controls. The mean values of absorbance in the ELISA assay of patients with ischemic heart disease (n=36, P<0.001), dilated cardiomyopathy (n=28, P<0.005), valvular heart disease (n=27, P<0.05), and collagen disease (n=38, P<0.05) were significantly higher than those of normal controls (n=53), but the value in patients with hypertrophic cardiomyopathy (n=19) was not significantly different from that of normal controls. When the cut-off value was fixed at the mean+2 SD of absorbance in normal controls, positive reactions were found in 19.4%, 7.1%, 18.5% and 15.8% of patients with ischemic heart disease, dilated cardiomyopathy, valvular heart disease, and collagen disease, respectively. An inhibition study revealed that anti-tropomyosin antibodies were different from anti-myosin antibodies, but there was a partial cross-reactivity between the two. Thus, there was a weak correlation of the titers of the two types of antibody within the group of heart diseases. These data indicate that measurement of anti-tropomyosin antibodies by ELISA is helpful for detecting autoimmune abnormalities in various heart diseases.
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PMID:Enzyme-linked immunosorbent assay for anti-tropomyosin antibodies and its clinical application to various heart diseases. 1090 Mar 3

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

Myocardial stunning is a form of reversible myocardial ischemia/reperfusion injury associated with systolic and diastolic contractile dysfunction. In the isolated rat heart model, myocardial stunning is characterized by specific C-terminal proteolysis of the myofilament protein, troponin I (cTnI) that yields cTnI1-193. To determine the effect of this particular C-terminal truncation of cTnI, without the confounding factor of other stunning-induced protein modifications, a series of solution biochemical assays has been undertaken using the human homologue of mouse/rat cTnI1-193, cTnI1-192. Affinity chromatography and actin sedimentation experiments detected little, or no, difference between the binding of cTnI (cTnI1-209) and cTnI1-192 to actin-tropomyosin, troponin T, or troponin C. Both cTnI and cTnI1-192 inhibit the actin-tropomyosin-activated ATPase activity of myosin subfragment 1 (S1), and this inhibition is released by troponin C in the presence of Ca2+. However, cTnI1-192, when reconstituted as part of the troponin complex (cTn1-192), caused a 54+/-11% increase in the maximum Ca2+-activated actin-tropomyosin-S1 ATPase activity, compared with troponin reconstituted with cTnI (cTn). Furthermore, cTn1-192 increased Ca2+ sensitivity of both the actin-tropomyosin-activated S1 ATPase activity and the Ca2+-dependent sliding velocity of reconstituted thin filaments, in an in vitro motility assay, compared with cTn. In an in vitro force assay, the actin-tropomyosin filaments bearing cTn1-192 developed only 76+/-4% (P<0.001) of the force obtained with filaments composed of reconstituted cTn. We suggest that cTnI proteolysis may contribute to the pathophysiology of myocardial stunning by altering the Ca2+-sensing and chemomechanical properties of the myofilaments.
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PMID:C-terminal truncation of cardiac troponin I causes divergent effects on ATPase and force: implications for the pathophysiology of myocardial stunning. 1455 Dec 40

Although the contribution of reactive oxygen species to myocardial ischemia is well recognized, the possible intracellular targets, especially at the level of myofibrillar proteins (MP), are not yet fully characterized. To assess the maximal extent of oxidative degradation of proteins, isolated rat hearts were perfused with 1 mM H(2)O(2). Subsequently, the MP maximally oxidative damage was compared with the effects produced by 1) 30 min of no-flow ischemia (I) followed in other hearts by 3 min of reperfusion (I/R); and 2) I/R in the presence of a potent antioxidant N-(2-mercaptopropionyl)glycine (MPG). Samples from the H(2)O(2) group electrophoresed under nonreducing conditions and probed with actin, desmin, or tropomyosin monoclonal antibodies showed high-molecular mass complexes indicative of disulfide cross-bridges along with splitting and thickening of tropomyosin and actin bands, respectively. Only these latter changes could be detected in I/R samples and were prevented by MPG. Carbonyl groups generated by oxidative stress on MP were detected by Western blot analysis (oxyblot) under optimized conditions. The analyses showed one major band corresponding to oxidized actin, the density of which increased 1.2-, 2.8-, and 6.8-fold in I, I/R, and H(2)O(2) groups, respectively. The I/R-induced increase was significantly reduced by MPG. In conclusion, oxidative damage of MP occurs on reperfusion, although at a lower extent than in H(2)O(2) perfused hearts, whereas oxidative modifications could not be detected in ischemic hearts. Furthermore, the inhibition of MP oxidation by MPG might underlie the protective efficacy of antioxidants.
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PMID:Evidence of myofibrillar protein oxidation induced by postischemic reperfusion in isolated rat hearts. 1476 72

Although a major contribution to myocardial ischemia-reperfusion (I/R) injury is suggested to be provided by formation of reactive oxygen species (ROS) within mitochondria, sites and mechanisms are far from being elucidated. Besides a dysfunctional respiratory chain, other mitochondrial components, such as monoamine oxidase and p66(Shc), might be involved in oxidative stress. In particular, p66(Shc) has been shown to catalyze the formation of H(2)O(2). The relationship among p66(Shc), ROS production and cardiac damage was investigated by comparing hearts from p66(Shc) knockout mice (p66(Shc-/-)) and wild-type (WT) littermates. Perfused hearts were subjected to 40 min of global ischemia followed by 15 min of reperfusion. Hearts devoid of p66(Shc) were significantly protected from I/R insult as shown by (i) reduced release of lactate dehydrogenase in the coronary effluent (25.7+/-7.49% in p66(Shc-/-) vs. 39.58+/-5.17% in WT); (ii) decreased oxidative stress as shown by a 63% decrease in malondialdehyde formation and 40+/-8% decrease in tropomyosin oxidation. The degree of protection was independent of aging. The cardioprotective efficacy associated with p66(Shc) ablation was comparable with that afforded by other antioxidant interventions and could not be increased by antioxidant co-administration suggesting that p66(Shc) is downstream of other pathways involved in ROS formation. In addition, the absence of p66(Shc) did not affect the protection afforded by ischemic preconditioning. In conclusion, the absence of p66(Shc) reduces the susceptibility to reperfusion injury by preventing oxidative stress. The present findings provide solid and direct evidence that mitochondrial ROS formation catalyzed by p66(Shc) is causally related to reperfusion damage.
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PMID:The cardioprotective effects elicited by p66(Shc) ablation demonstrate the crucial role of mitochondrial ROS formation in ischemia/reperfusion injury. 1936 67

There is evidence for an inverse association between cellular expression of Hsp27 and vascular disease with carotid plaques, endarterectomy specimens, and cardiac biopsies investigated to date. Here we compare non-diseased coronary arteries from human heart transplant donors and patients with dilated cardiomyopathy (DCM) with no evidence of coronary artery disease, to coronary arteries from patients with ischemic heart disease (IHD) in order to determine abundance of phosphorylated Hsp27 (phospho-Hsp27) in plaque-free diseased vessels and elucidate how this protective effect is brought about through protein regulation. Western blotting identified phospho-Hsp27, phosphorylated on Ser82, Ser78, and Ser15, to be specifically decreased in IHD, but not DCM, compared to non-diseased vessels. Immunohistochemistry confirmed these results and revealed phospho-Hsp27 was located within both smooth muscle and endothelial cells. Disease-free coronary arteries and from patients with IHD were then subjected to 2-Dimensional Difference Gel Electrophoresis (2D-DIGE) analysis to detect proteins with altered abundance, which were subsequently identified by mass spectrometry. Hsp27 showed decreased abundance in ischemic vessels as expected. The expression of cytoskeletal proteins, namely vimentin was significantly reduced, while transgelin and tropomyosin showed significantly increased abundance in vessels with IHD. Immunohistochemistry studies suggested an increase in G-actin abundance to be present within IHD vessels. The results are consistent with the hypothesis that phospho-Hsp27 protects against vascular disease possibly by stabilizing the actin cytoskeleton within endothelial and/or smooth muscle cells.
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PMID:Protective effect of phosphorylated Hsp27 in coronary arteries through actin stabilization. 2060 Jan 3