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)

Cardiomyocytes are post-mitotic, long-lived cells until disruptions to pro-survival factors occur after myocardial ischemia. To gain an understanding of the factors involved with ischemic injury, we examined expression changes in pro-survival and opposing pro-apoptotic signals at early and chronic periods of ischemia using an in vivo murine model. Alterations of pro-survival proteins such as the inhibitor of apoptosis protein on chromosome X (xIAP) and the apoptotic repressor protein (ARC) have not been evaluated in a murine model of cardiac ischemia. Early ischemia (1 day) resulted in a 50% reduction in ARC protein levels relative to sham-operated left ventricles, without significant changes in the expression of xIAP or other pro-survival factors. In contrast, a deficiency of xIAP expression was found in cardiac infarcts starting after 1 week, concomitant with significant evidence of apoptotic cell death and an up-regulation of pro-apoptotic signals including Bax, tumor necrosis factor-a, and caspase-8 activation. Chronic ischemia (after 2 weeks) was associated with elevated levels of other pro-survival factors such as Bcl-xL and the phosphorylated form of Akt, as part of the adaptive remodeling of the myocardium. Altogether, these findings suggest that strategies to increase IAP expression may promote myocyte survival after chronic ischemia.
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PMID:Ischemia elicits a coordinated expression of pro-survival proteins in mouse myocardium. 1280 54

Efficient induction of apoptosis requires not only the activation of death-promoting proteins but also the inactivation of inhibitors of cell death. ARC (apoptosis repressor with caspase recruitment domain) is an endogenous inhibitor of apoptosis that antagonizes both central apoptosis pathways. Despite its potent inhibition of cell death, cells that express abundant ARC eventually succumb. A possible explanation is that ARC protein levels decrease dramatically in response to death stimuli. The mechanisms that mediate decreases in ARC protein levels during apoptosis and whether these decreases initiate the subsequent cell death are not known. Here we show that endogenous ARC protein levels decrease in response to death stimuli in a variety of cell contexts as well as in a model of myocardial ischemia-reperfusion in intact mice. Decreases in ARC protein levels are not explained by alterations in the abundance of ARC transcripts. Rather, pulse-chase experiments show that decreases in steady state ARC protein levels during apoptosis result from marked destabilization of ARC protein. ARC protein destabilization, in turn, is mediated by the ubiquitin-proteasomal pathway, as mutation of ARC ubiquitin acceptor residues stabilizes ARC protein and preserves its steady state levels during apoptosis. In addition, this degradation-resistant ARC mutant exhibits improved cytoprotection. We conclude that decreases in ARC protein levels in response to death stimuli are mediated by increased ARC protein degradation via the ubiquitin-proteasomal pathway. Moreover, these data demonstrate that decreases in ARC protein levels are a trigger, and not merely a consequence, of the ensuing cell death.
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PMID:The apoptosis inhibitor ARC undergoes ubiquitin-proteasomal-mediated degradation in response to death stimuli: identification of a degradation-resistant mutant. 1714 52

A plethora of apoptotic stimuli converge on the mitochondria and affect their membrane integrity, thereby eliciting release of multiple death-promoting factors residing in the mitochondrial intermembrane space into the cytosol. Among the death-promoting factors, a serine protease, high temperature requirement A2 (HtrA2) has drawn attention as a key player in the apoptosis pathways in different pathological conditions including myocardial ischemia/reperfusion injury. Heart ischemia/reperfusion results in HtrA2 translocation from the mitochondria to the cytosol, where it promotes cardiomyocyte apoptosis via a protease activity-dependent and caspase-mediated pathway. Once released, cytosolic HtrA2 causes X-chromosome-linked inhibitor of apoptosis protein (XIAP) degradation, caspase activation, and subsequent apoptosis. Consistent with the hypothesis, inhibition of HtrA2 improved postischemic myocardial contractile functions along with reduction of myocardial infarct size. The precise mechanism underlying HtrA2-induced apoptosis in mammalian cells has been studied through biochemical, structural, and genetic studies, in which HtrA2 promotes proteolytic activation of caspases through multiple pathways in heart ischemia. Therapeutic interventions that inhibit HtrA2 expression, translocation, or protease activity (such as by using the ucf-101 inhibitor) may provide an attractive therapeutics in the treatment of cardiovascular diseases.
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PMID:Activation of HtrA2, a mitochondrial serine protease mediates apoptosis: current knowledge on HtrA2 mediated myocardial ischemia/reperfusion injury. 1878 92

B-type natriuretic peptide (BNP) is one peptide hormone released in response to myocyte stretch, whose functions play significant roles in health and disease. Its physiologic effects result in improved loading conditions and have led to the development of recombinant BNP as a therapeutic agent for heart failure. Previous work has identified that BNP protect myocardium against reperfusion injury through mitochondrial pathway. Mitochondria are both essential effectors of cardioprotection and primary targets of cardioprotective signaling. Their role during reperfusion is particularly critical because of the conditions that promote both apoptosis by the mitochondrial pathway and necrosis by irreversible damage to mitochondria in association with mitochondrial permeability transition pores (mPTP). After an episode of myocardial ischemia, opening of mPTP, at the onset of reperfusion, is a critical determinant of myocyte death. The relationship of BNP and mPTP in mediating reperfusion-induced cardiomyocytes injury is a novel investigative area. In this study, our results indicated that the beneficial effect of BNP in cultured cardiomyocytes subjected to reperfusion is associated with attenuation of mPTP opening, resultant mitochondrial dysfunction and apoptosis. Further investigation of underlying mechanisms revealed that these were associated with BNP-mediated repolarization of mitochondrial membrane potential (Deltapsi(m)), inhibition of reactive oxygen species (ROS) generation, improvement of Bcl-2 level, and inhibition of Bax and second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein-binding protein with a low isoelectric point (Smac/DIABLO) levels. In summary, we demonstrate that BNP exerts protective actions within reperfusion by inhibiting mPTP opening and these roles of BNP may involve phosphatidylinositol 3-kinase (PI3K) dependent pathway.
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PMID:B-type natriuretic peptide-induced cardioprotection against reperfusion is associated with attenuation of mitochondrial permeability transition. 1972 Dec 30

Survival after acute myocardial infarction is decreased in elderly patients. The enhanced rates of apoptosis in the aging heart exacerbate myocardial ischemia/reperfusion (MI/R) injury. We have recently demonstrated that the X-linked inhibitor of apoptosis protein (XIAP), the most potent endogenous inhibitor of apoptosis, was decreased in aging rats' hearts. XIAP was balanced by two mitochondria proteins, Omi/HtrA2 and Smac/DIABLO. However, the implicative role of XIAP, Omi/HtrA2, and Smac/DIABLO to aging-related MI/R injury has not been previously investigated. In our study, male aging rats (20-24 months) or young adult rats (4-6 months) were subjected to 30 min of myocardial ischemia followed by reperfusion. MI/R-induced cardiac injury was enhanced in aging rats, as evidenced by aggravated cardiac dysfunction, enlarged infarct size, and increased myocardial apoptosis (TUNEL and caspase-3 activity). Then, the XIAP, Omi/HtrA2, and Smac/DIABLO protein and mRNA expression was detected. XIAP protein and mRNA expression was decreased in both aging hearts and aging hearts subjected to MI/R. Meanwhile, myocardial XIAP protein expression was correlated to cardiac function after MI/R. However, Omi/HtrA2, but not Smac/DIABLO, expression was increased in aging hearts. Moreover, the translocation of Omi/HtrA2 from mitochondria to cytosol was increased in both aging hearts and aging hearts subjected to MI/R. Treatment with ucf-101 (a novel and specific Omi/HtrA2 inhibitor) attenuated XIAP degradation and caspase-3 activity and exerted cardioprotective effects. Taken together, these results demonstrated that increased expression and leakage of Omi/HtrA2 enhanced MI/R injury in aging hearts via degrading XIAP and promoting myocardial apoptosis.
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PMID:Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death : Omi/HtrA2 and aged heart injury. 2253 53

It is generally accepted that insulin exerts an antiapoptotic effect against ischemia/reperfusion through the activation of PI3K/Akt/mTOR pathway. MicroRNAs involve in multiple cardiac pathophysiological processes, including ischemia/reperfusion-induced cardiac injury. However, the regulation of microRNAs in the cardioprotective effect of insulin is rarely discussed. In this study, using a cell model of ischemia through culturing H9C2 cardiac myocytes in serum-free medium with hypoxia, we demonstrated that pretreatment with insulin significantly inhibited cell apoptosis and downregulated microRNA-320 (miR-320) expression. Interestingly, miR-320 mimic impaired the cardioprotective effect of insulin against myocardial ischemia injury by targeting survivin, which is a member of the family of inhibitor of apoptosis proteins. Suppression miR-320 expression by miR-320 inhibitor in H9C2 cells with myocardial ischemia mimics the cardioprotective effect of insulin by maintaining survivin expression. Taken together, miR-320-mediated survivin expression involves in cardioprotective effect of insulin against myocardial ischemia injury.
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PMID:MicroRNA-320 involves in the cardioprotective effect of insulin against myocardial ischemia by targeting survivin. 2952 36