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)

alpha B crystallin, a heat-shock-like protein, is a major component of the soluble protein fraction of the heart and is thought to play a protective role in stress situations. During an ischemic episode, the cytosol of cardiomyocytes acidifies, thus causing the aggregation of the protein with cytoskeletal elements. After homogenization of the tissue, alpha B crystallin can then be recovered with the insoluble cell components. This study investigated the change of the solubility properties of crystallin in the ischemic heart. The distribution of crystallin in the soluble and insoluble cellular fractions was determined by centrifugation of heart homogenates and immunoblot analysis with anti-alpha B crystallin antibodies. The proportion of aggregated alpha B-crystallin increased in hearts reperfused after total normothermic ischemia of increasing severity. alpha B crystallin aggregation was proportional to the amount of lactate dehydrogenase activity released by the hearts and was inversely correlated to the ability of the hearts to recover contractile activity after the ischemic episode. This study shows that the amount of aggregated crystallin can be used as a new marker for the ischemic damage of the heart. Biopsies of a few milligrams are sufficient for the analysis.
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PMID:Determination of alpha B crystallin aggregation: a new alternative method to assess ischemic damage of the heart. 156 52

alpha B-Crystallin is a 20-kd peptide highly homologous to the small heat-shock proteins. This protein forms soluble homomultimeric complexes (M(r), 300-700 kd) and is very abundant in cardiac muscle cells. In vitro experiments (affinity column chromatography and binding studies with isolated proteins) have shown that alpha B-crystallin interacts directly with actin and, in particular, with desmin filaments. The immunocytochemical localization of alpha B-crystallin within the cardiomyocytes showed that the protein is distributed exclusively in the central region of the I bands (Z lines), where desmin is localized. In vitro studies have further shown that the binding affinity of alpha B-crystallin to actin and desmin filaments increases considerably at slightly acidic pH (6.5) or after a heat treatment (45 degrees C). Moreover, alpha B-crystallin was found to prevent effectively the tendency of actin filaments to form aggregates (i.e., paracrystals) at acidic pH. These in vitro data suggest a protective role of alpha B-crystallin during stress conditions such as ischemia of the heart. Crystallin could prevent the aggregation of filaments, which might occur during the acidification of the cytosol and lead eventually to irreversible structural damage.
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PMID:Alpha B-crystallin in cardiac tissue. Association with actin and desmin filaments. 162 87

Myofibrillar proteins (MPs) were extracted from isolated and perfused rat hearts subjected to different periods of ischemia to investigate the occurrence of protein degradation and/or the association of cytosolic proteins with the myofibrillar pellet. A 23-kD band was detected by SDS-PAGE of MPs after 5 minutes of ischemia, with its density gradually increasing to a plateau after 20 minutes. Longer periods of ischemia were associated with the appearance of a 39-kD band. Irrespective of the duration of ischemia, both these bands persisted during reperfusion. A partial proteolytic degradation of troponin T (TnT) and troponin I (TnI) has been claimed to be responsible for the generation of these peptides. However, the N-terminal sequence of the 39-kD band was identical to that of GAPDH, whereas Edman sequencing after pepsin digestion showed that the 23 kD is alpha B-crystallin. The binding of the two cytosolic proteins to myofibrils was confirmed by immunofluorescence analysis on cryosections of ischemic hearts. In vitro studies showed that acidosis was sufficient to induce the binding of alpha B-crystallin, whereas the inhibition of ATP depletion prevented the binding of GAPDH. Thiol oxidation is unlikely to promote GAPDH binding, since perfusion with iodoacetate under aerobic conditions or treatment of homogenates with N-ethylmaleimide or diamide failed to induce GAPDH association with the myofibrils. These changes of the myofibrillar proteins could be considered as intracellular markers of the evolution of the ischemic damage. In addition, the binding of the 23-kD peptide might be involved in alterations of contractility.
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PMID:Binding of cytosolic proteins to myofibrils in ischemic rat hearts. 862 Jun 2

It is becoming clear that stress proteins play a role in various aspects of postischemic myocardial recovery and that the cytoskeleton of cardiac myocytes is an important determinant for cellular survival during ischemia and energy depletion. In the present study, we addressed the question of whether the cytoskeleton-binding stress protein alpha B-crystallin may be involved in early cellular responses of rat and porcine myocardium to ischemia. Immunostaining and subcellular fractionation revealed a rapid ischemia-induced redistribution of alpha B-crystallin from a cytosolic pool to intercalated disks and Z lines of the myofibrils. This striking translocation of alpha B-crystallin from the cytosol to sites of the myofibrillar system that are known to be sensitive to ischemia-reperfusion injury was accompanied by a rapid shift of a fraction of alpha B-crystallin to a more acidic isoelectric point. This shift is caused by alpha B-crystallin phosphorylation, as identified by its augmentation in the presence of phosphatase inhibitors (vanadate, fluoride) and comigration of the acidic alpha B-crystallin form with the phosphorylated B1 form of lenticular alpha B-crystallin. In view of the chaperone-like function of alpha B-crystallin in conjunction with its high level of constitutive expression in the myocardium (1-2% of soluble protein content), we consider alpha B-crystallin an excellent candidate to play a role in early aspects of the protection of the myocardial contractile apparatus against ischemia-reperfusion injury.
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PMID:Ischemia-induced phosphorylation and translocation of stress protein alpha B-crystallin to Z lines of myocardium. 961 50

Stress proteins are assumed to protect cells against various kinds of stresses including ischemia. In this study, we focused on the behaviour of the most abundant myocardial stress protein, alpha B-crystallin, during ischemia and reperfusion of the pig heart in vivo, alpha B-crystallin constitutes 1-2% of the soluble protein pool and underwent, during severe but reversibly damaging ischemia (25 min), complete translocation to the Z-line area of myofibrils. Irreversibly damaging ischemia (60 min) was accompanied by extreme stretching of the majority of myofibrils, and by concomitant extension of alpha B-crystallin localization from the Z-line area to I-bands. This I-band shift correlated with displacement of the T12 epitope of titin from the vicinity of Z-lines into I-bands, indicating that the primary binding sites for alpha B-crystallin might also be located in juxtaposition to Z-lines and move into the I-bands during extreme sarcomeric stretching. During reperfusion after 25 min of ischemia, alpha B-crystallin disappeared rapidly from myofibrils: whereas reperfusion after irreversibly damaging ischemia (60 min) resulted in dissociation of alpha B-crystallin only from those myofibrils and myocardiocytes that were still able to contract, and alpha B-crystallin remained bound to the overstretched, damaged myofibrils no longer capable of contraction. The time course of translocation of alpha B-crystallin to myofibrils during ischemia correlated with phosphorylation of approximately 20% of the entire alpha B-crystallin pool. However, disappearance of alpha B-crystallin from myofibrils during reperfusion was not accompanied by dephosphorylation, indicating that phosphorylation alone does not explain myofibrillar binding of alpha B-crystallin. Ischemia-induced myofibrillar targeting of alpha B-crystallin probably requires additional structural and posttranslational modifications of myofibrillar components in juxtaposition to I-bands.
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PMID:Binding of the stress protein alpha B-crystallin to cardiac myofibrils correlates with the degree of myocardial damage during ischemia/reperfusion in vivo. 1019 88

Heat shock proteins present a complex family of proteins exerting chaperone-like activities that are classified according to their molecular weight. We especially explored protective functions of inducible heat shock protein 70, the mitochondrial heat shock protein 60 and 10, and the small heat shock proteins HSP27 and alphaB-crystallin against ischemic, reoxygenation-mediated injury using transgenic animals and hearts under in vivo conditions and in isolated cardiac myocyte-derived cells using adenoviral vectors. We noted with great interest that differential protective effects are exerted by specific hsps. For example, alpha-B-crystallin and constitutive hsp70 markedly protect microtubular structure in cardiac myocytes from ischemia-induced injury. Inducible hsp70, hsp60 and hsp10 when coexpressed, and hsp27 and alphaB-crystallin have an overall protective effect against ischemic injury as determined by the release of enzymes like creatine kinase and LDH. We did not note inflammatory or immune responses elicited by the expression of hsps in transgenic animals and cardiac myocytes. The specific cell types in which hsps are expressed may contribute to the protective effect of hsps versus their inflammatory and immunogenic effects when expressed in other cell types.
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PMID:Heat shock proteins and protection against ischemic injury. 1023 Oct 10

Small heat shock proteins (sHSPs), a family of HSPs, are known to accumulate in the CNS, mainly in astrocytes, in several pathological conditions such as Alexander's disease, Alzheimer's disease, and Creutzfeldt-Jakob disease. sHSPs may act not only as molecular chaperones, protecting against various stress stimuli, but may also play a physiological role in regulating cell differentiation and proliferation. In the present study, we have demonstrated that transient focal ischemia in rats dramatically induced HSP27 but not alpha B-crystallin (alphaBC), both of which are members of sHSPs, in reactive astrocytes. In contrast, in vitro chemical ischemic stress induced both HSP27 and alphaBC in cultured glial cells to the same extent. Dibutyryl cAMP (dBcAMP) and isoproterenol, a beta-adrenergic receptor (betaAR) agonist, enhanced HSP27 expression but suppressed alphaBC, and changed the shape of the cells to a stellate form. dBcAMP and isoproterenol inhibited cell proliferation under normal conditions. An increase in betaAR-like immunoreactivity was also observed in reactive astrocytes in vivo. These results, together with recent findings that betaAR plays an important role in glial scar formation in vivo, raise the possibility that betaAR activation modulates sHSP expression after focal ischemia and is involved in the transformation of astrocytes to their reactive form.
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PMID:Differential expression of small heat shock proteins in reactive astrocytes after focal ischemia: possible role of beta-adrenergic receptor. 1055 86

During ischemia the cardiac stress protein, alpha B-crystallin, was shown by immunoelectron microscopy to translocate to the N(2)-line area of myofibrillar I-bands of rat cardiomyocytes where alpha B-crystallin resisted extraction with 1 m NaSCN and 2 m urea as did titin. Actin became completely extracted under these conditions, indicating association of alpha B-crystallin with titin the only remaining non-actin cytoskeletal component of I-bands outside Z-disks. Titin, extracted from ischemic pig myocardium, was shown to copurify with alpha B-crystallin. Further evidence for binding of alpha B-crystallin to titin was obtained by dot-blot assays in which biotinylated alpha B-crystallin was demonstrated to bind to the titin-enriched fraction immobilized on nitrocellulose. Binding of alpha B-crystallin to titin during cardiac ischemia could serve to stabilize titin against denaturation and might provide an endogenous mechanism to delay ischemic damage of this important elastic component of myofibrils.
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PMID:Ischemia-induced association of the stress protein alpha B-crystallin with I-band portion of cardiac titin. 1194 23

High levels of alpha B-crystallin are present in the cardiomyocyte, yet little is understood about the function and importance of this protein. Like many other small heat shock proteins, alpha B-crystallin forms large oligomeric complexes whose size can be regulated by posttranslational modifications. The size of these complexes can modify the function of the protein. A naturally occurring COOH-terminal mutant has many detrimental effects in the lens of the eye and altered oligomerization. Therefore, we mutated the two COOH-terminal lysines of alpha B-crystallin to glycines (K174/175G) and adenovirally mounted them to transduce cardiomyocytes. We analyzed the effect of this mutation on oligomerization, microtubular stabilization, and ischemic outcome. A nearly 45% downward shift in complex size was observed with the mutant by native PAGE followed by immunoblotting. The overexpressed protein no longer protected the tubulin cytoskeleton against ischemic stress by confocal analysis. The mutant caused a 30% increase in cytosolic enzyme release with ischemia compared with control, whereas a 33% decrease was associated with wild-type alpha B-crystallin overexpression. We conclude that the COOH terminus of alpha B-crystallin is crucial to its proper function.
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PMID:Mutation of COOH-terminal lysines in overexpressed alpha B-crystallin abrogates ischemic protection in cardiomyocytes. 1206 78

The mitogen-activated protein kinases (MAPK) have been the subject of many studies to identify signaling pathways that promote cell survival or death. In cultured cardiac myocytes, p38 MAPK promotes cell survival or death depending on whether it is activated by mitogen-activated protein kinase kinase 6 (MKK6) or MKK3, respectively. The objectives of the current study were to examine the effects of MKK6-mediated p38 activation in the heart in vivo. Accordingly, we generated transgenic (TG) mice that overexpress wild type MKK6 in a cardiac-restricted manner. Although p38 was about 17-fold more active in TG than non-transgenic (NTG) mouse hearts, TG mouse hearts were morphologically and functionally similar to those of NTG littermates. However, upon transient ischemia followed by reperfusion, the MKK6 TG mouse hearts exhibited significantly better functional recovery and less injury than NTG mouse hearts. Because MKK6 increases levels of the protective small heat shock protein, alpha B-crystallin (alpha BC), in cultured cardiac myocytes, we examined alpha BC levels in the mouse hearts. The level of alpha BC was 2-fold higher in MKK6 TG than NTG mouse hearts. Moreover, ischemia followed by reperfusion induced a 6.4-fold increase in alpha BC levels in the mitochondrial fractions of TG mouse hearts but no increase in alpha BC levels in any of the other fractions analyzed. These alterations in alpha BC expression and localization suggest possible mechanisms of cardioprotection in MKK6 TG mouse hearts.
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PMID:Overexpression of mitogen-activated protein kinase kinase 6 in the heart improves functional recovery from ischemia in vitro and protects against myocardial infarction in vivo. 1549 8


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