Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Changes of structural proteins in experimental and human myocardial infarction were studied by the determination of myosin- and actomyosin-ATPase activities and gel electrophoretic analysis in the presence of sodium dodecyl sulfate (SDS). 2. In animal experiments using dogs, the relative amounts of myosin and alpha-actinin decreased at 24 to 48 hours after coronary ligation, became lowest at 72 hours, and remained at this level for 2 weeks and returned to almost normal value at 28 days. 3. Myosin- and actomyosin-ATPase activities decreased rapidly during 24 to 48 hours after ligation with temporary increase in their activities in the initial stage of ischemia and followed the similar time course as that of the amounts of myosin and alpha-actinin. 4. SDS gel electrophoretic analysis of structural proteins of infarcted tissues of the human hearts obtained from 5 cadavers showed also marked decrease of the contents of myosin and alpha-actinin with relative preservation of actin, tropomyosin and troponin-T.
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PMID:Changes of cardiac structural proteins in myocardial infarction. 92 15

Past studies of acute canine right ventricular (RV) ischemia have failed to demonstrate early irreversible injury or decreased function; however, the dog has extensive collateral circulation that may attenuate RV myocardial injury. The aim of this study was to measure RV function using contrast ventriculography and assess myocardial injury by immunohistochemical evaluation of creatine kinase (CK), lactate dehydrogenase (LDH), and tropomyosin (TROP) as well as by electron microscopy after right coronary occlusion in 14 closed-chest pigs. Significant depression in RV ejection fraction and stroke volume index after 10 minutes and was observed (P less than 0.05). CK, LDH, and TROP were positive in control tissue with a diminution of CK and LDH staining along the subendocardium after 15 minutes of ischemia. Irreversible ultrastructural injury in conjunction with large losses of CK and LDH became evident after 30 minutes. Thus, in the pig, which has a coronary anatomy similar to humans, significant RV dysfunction and irreversible myocardial injury can be demonstrated after 15 to 30 minutes of ischemia.
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PMID:Demonstration of early ischemic injury in porcine right ventricular myocardium. 292 87

Acute exposure of the heart to ethanol does not appear to alter the rate of young guinea pig cardiac protein synthesis when assayed in vitro. In contrast, the primary metabolite of ethanol, acetaldehyde, markedly diminishes synthesis despite its chronotropic and inotropic effects. On the other hand, after 11-13 weeks of ethanol-drinking during growth and maturation, the synthetic capacity of the working right ventricle was decreased when measured in vitro with normal perfusate. Assay of synthesis of the contractile proteins myosin heavy and light chains, actin and tropomyosin suggests a change in synthesis or pool size of actin reflected in an alteration of relative synthesis of this protein compared to that of heavy chains. The relative synthesis of the other proteins remained at control levels. When hearts from ethanol-drinking and matched control animals were perfused under conditions of severe ischemia, there was a profound fall in protein synthesis in all hearts, and ethanol did not enhance the inhibition of synthesis. However, the hearts from ethanol-drinking animals showed a more marked and significant impairment of maintaining ejection pressure with a marked increase in coronary resistance as the perfusion progressed. It is postulated that some impairment of protein metabolism may occur during prolonged ethanol exposure, which may influence the cardiac response of another induced stress, e.g., ischemia.
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PMID:Ethanol and cardiac protein synthesis. 391 35

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

Myocardial stunning is characterized by decreased myofilament Ca2+ responsiveness. To investigate the molecular basis of stunned myocardium, we performed PAGE and Western immunoblot analysis of the contractile proteins. Isolated rat hearts were retrogradely perfused at 37 degrees C for either 50 minutes (control group) or for 10 minutes, followed by 20-minute global ischemia and 20-minute reperfusion (stunned group), or for 20-minute ischemia without reflow. Another group consisted of hearts subjected to 20-minute ischemia in which stunning was mitigated by 10-minute reperfusion with low Ca2+/low pH solution. Myocardial tissue samples subjected to PAGE revealed no obvious differences among groups. Western immunoblots for actin, tropomyosin, troponin C, troponin T, myosin light chain-1, and myosin light chain-2 showed highly selective recognition of the appropriate full-length molecular weight bands in all groups. Troponin I (TnI) Western blots revealed an additional band (approximately 26 kD, compared with 32 kD for the full-length protein) in stunned myocardial samples only. In parallel experiments, skinned trabeculae were treated with calpain I for 20 minutes; Western blots showed a TnI degradation pattern similar to that observed in stunned myocardium. Such TnI degradation was prevented by calpastatin, a naturally occurring calpain inhibitor. The results show that (1) TnI is partially and selectively degraded in stunned myocardium; (2) this degradation could be prevented by low Ca2+/low pH reperfusion, which also prevented the contractile dysfunction of stunning; and (3) calpain I could similarly degrade TnI, supporting the idea that Ca(2+)-dependent myofilament proteolysis underlies myocardial stunning.
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PMID:Role of troponin I proteolysis in the pathogenesis of stunned myocardium. 904 60

Our objective in experiments reported here was to identify myofilament proteins of rat hearts either lost or degraded by cardiac ischemia (15- or 60-minute duration) with and without 45 minutes of reperfusion. We correlated these changes with alterations in myofilament sensitivity to Ca2+ and maximum force generation. Protein degradation and loss were assessed by high-performance liquid chromatography, SDS-PAGE, Western blotting analysis, and amino acid sequencing. Compared with nonischemic control hearts, bundles of skinned fibers from hearts subjected to ischemia alone demonstrated a decrease in maximum force generation and an increase in sensitivity to Ca2+. These changes in function were increased with the duration of the ischemia and with reperfusion. With increasing duration of ischemia, there was an increased loss and degradation of myofibrillar alpha-actinin and troponin I (TnI) at its C-terminus. Alpha-actinin and TnI were most susceptible to ischemia, but with 60 minutes of ischemia/reperfusion, there was also degradation of myosin light chain-1 (MLC1) involving a clip of residues 1 to 19. The MLC1 degradation product was detected in the reperfusion effluent (along with troponin T, tropomyosin, and alpha-actinin) but not in the tissue with 60 minutes of ischemia with no reperfusion. Moreover, with ischemia the following proteins became associated with the myofibrils: GAPDH and proteins of the mitochondrial ATP synthase complex. Our results provide new evidence regarding the mechanism by which ischemia/reperfusion causes myocardial injury and support the hypothesis that an important element in the injury is altered activity and structure of the myofilaments.
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PMID:Breakdown and release of myofilament proteins during ischemia and ischemia/reperfusion in rat hearts: identification of degradation products and effects on the pCa-force relation. 946 97

We present a current perception of the regulation of activation of cardiac myofilaments with emphasis on troponin (Tn) and tropomyosin (Tm). Activation involves both a Ca2+-regulated molecular switch and a potentiated state, dependent on feedback effects of force-generating crossbridges. Recent developments in the elucidation of the structure and arrangement of the myofilament proteins offer insights into the molecular interactions that constitute the switching and potentiating mechanisms. Transgenic mice overexpressing myofilament proteins, in vitro studies of mutant myofilament proteins, multidimensional multinuclear nuclear magnetic resonance, and fluorescence resonance energy transfer offer important approaches to understanding the molecular signaling processes. These studies reveal special features of the cardiac myofilament proteins that appear specialized for the unique functions of the heart. An important aspect of these special features is their role in mechanical, chemical, and neurohumoral coupling processes that tune myofilament activation to hemodynamics and beating frequency. Understanding these processes has become essential to understanding cardiac pathologies such as heart failure, ischemia and reperfusion injury, stunning, and familial hypertrophic cardiac myopathies.
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PMID:Troponin and tropomyosin: proteins that switch on and tune in the activity of cardiac myofilaments. 973 69

The regulatory protein troponin (Tn) located on actin filament consists of three subunits: TnT--binds troponin to tropomyosin, TnC--binds divalent calcium ions, and TnI--affects myosin-actin interactions. Tn subunits display several molecular and calcium binding variations. During ontogenetic development of cardiac and skeletal muscles the synthesis of multiple isoforms of Tn subunits was detected. Expression of Tn isoforms and the extent of phosphorylation of both TnT and TnI via protein kinase C or protein kinase A under different pathological situations (e.g. ischemia, congenital heart disease, heart failure) can affect the Ca2+-stimulated contraction function and the myofibrillar ATPase activity of the heart.
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PMID:Isoforms of troponin in normal and diseased myocardium. 1063 75

In contrast to skeletal muscle, the efficiency of the contractile apparatus of cardiac tissue has long been known to be severely compromised by acid pH as in the ischemia of myocardial infarction and other cardiac myopathies. Recent reports (Westfall, M. V., and Metzger, J. M. (2001) News Physiol. Sci. 16, 278-281; Li, G., Martin, A. F., and Solaro, R. J. (2001) J. Mol. Cell. Cardiol. 33, 1309-1320) have indicated that the reduced Ca(2+) sensitivity of cardiac contractility at low pH (<or=pH 6.5) is attributable to structural difference(s) in the cardiac and skeletal inhibitory components (TnIs) of their troponins. Here, using a reconstituted Ca(2+)-regulated human cardiac troponin-tropomyosin actomyosin S1 ATPase assay, we report that a single TnI mutation, A162H, restores Ca(2+) sensitivity at pH 6.5 to that at pH 7.0. Levels of inhibition (pCa 7.0), activation (pCa 4.0), and cooperativity of ATPase activity were minimally affected. Two other mutations (Q155R and E164V) also previously suggested by us (Pearlstone, J. R., Sykes, B. D., and Smillie, L. B. (1997) Biochemistry 36, 7601-7606) and involving charged residues showed no such effects. With fast skeletal muscle troponin, a single TnI H130A mutation reduced Ca(2+) sensitivity at pH 6.5 to levels approaching the cardiac system at pH 6.5. These observations provide structural insight into long-standing physiological and clinical phenomena and are of potential relevance to therapeutic treatments of heart disease by gene transfer, stem cell, and cell transplantation approaches.
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PMID:Single mutation (A162H) in human cardiac troponin I corrects acid pH sensitivity of Ca2+-regulated actomyosin S1 ATPase. 1215 82


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