UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pain thresholds in humans were determined for heat stimulations of the skin before and after a mild injury induced by a single conditioning stimulus (CS) of 50 degrees C and 100 sec duration. The same stimuli were delivered to the receptive fields of C fiber and A fiber mechanoheat-sensitive nociceptors (CMH and AMH nociceptors, respectively) and of low threshold warm and cold receptors in the anesthetized monkey and to the receptive fields of CMH nociceptors recorded percutaneously from the peroneal nerve of awake humans. Pain thresholds in normal skin were matched only by the response thresholds of CMH and not AMH nociceptors. Immediately following heat injury, some pain thresholds and CMH response thresholds were elevated, but by 5 to 10 min after the CS, pain and CMH thresholds were lowered to 2 to 6 degrees C below normal (hyperalgesia and nociceptor sensitization). No other type of cutaneous receptor studied exhibited changes in threshold similar to those observed for pain and for CMH nociceptors. The magnitude of hyperalgesia in humans and the magnitude of sensitization of CMH nociceptors in monkeys following heat injury were greater for hairy than for glabrous skin. The time course of the development of hyperalgesia was not altered by ischemia or conduction block in A fibers. The results support the conclusion that altered activity in CMH nociceptors is a major peripheral determinant of cutaneous hyperalgesia following a mild heat injury to the skin.
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PMID:Peripheral neural mechanisms of cutaneous hyperalgesia following mild injury by heat. 708 82

Nitric oxide synthase (NOS) is believed to play an important role in protecting the myocardium against ischemia. Chronic hypoxia from birth increases NOS activity in the myocardium resulting in enhanced nitric oxide production and increased resistance to ischemia. We examined the effects of chronic hypoxia on NOS gene and protein expression and on NOS protein association with caveolin-3. Rabbits were raised from birth in a normoxic (F(I)O(2) = 0.21) or a hypoxic (F(I)O(2) = 0.12) environment for 9 d, and then the hearts were isolated. Ribonuclease protection assays revealed that chronic hypoxia did not alter NOS transcript levels for NOS1, NOS2, or NOS3. The most abundant transcript was NOS3. Western analysis revealed NOS3 was the only isoform detected. Immunoblots of NOS3 immunoprecipitates showed that chronic hypoxia increases NOS3 protein by 2.0 +/- 0.4-fold and decreases the amount of caveolin-3 that can be coprecipitated with NOS3 by 5.5 +/- 0.9-fold. Immunoblots of normoxic and hypoxic hearts showed that chronic hypoxia decreases the amount of caveolin-3 in heart homogenates by 2. 2 +/- 0.5-fold. These data suggest that a decrease in caveolin-3 plays a role in the mechanisms by which chronic hypoxia increases NOS3 activity in the myocardium.
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PMID:Chronic myocardial hypoxia increases nitric oxide synthase and decreases caveolin-3. 1105 70

A loss of sarcolemmal dystrophin was observed by immuno-fluorescence studies in rabbit hearts subjected to in situ myocardial ischemia and by immuno-blotting of the Triton soluble membrane fraction of isolated rabbit cardiomyocytes subjected to in vitro ischemia. This ischemic loss of dystrophin was a specific event in that no ischemic loss of sarcolemmal alpha-sarcoglycan, gamma-sarcoglycan, alphaDG, or betaDG was observed. The maintenance of sarcolemmal betaDG (43 Kd) during ischemia was interesting in that dystrophin binds to the C-terminus of betaDG. However, during late in vitro ischemia, a 30 Kd band was observed that was immuno-reactive for betaDG. Additionally, this 30 Kd-betaDG band was observed in rabbit myocardium subjected to autolysis. Finally, the 30 Kd-betaDG was observed in the purified sarcolemmal fraction of rabbit cardiomyocytes subjected to a prolonged period of in vitro ischemia, confirming the sarcolemmal localization of this band. The potential patho-physiologic significance of this band was indicated by the appearance of this band at 120-180 min of in vitro ischemia, directly correlating with the onset of irreversible injury, as manifested by osmotic fragility. Additionally the appearance of this band was significantly reduced by the endogenous cardioprotective mechanism, in vitro ischemic preconditioning, which delays the onset of osmotic fragility. In addition to dystrophin, betaDG binds caveolin-3 and Grb-2 at its C-terminus. The presence of Grb-2 and caveolin-3 in the membrane fractions of oxygenated and ischemic cardiomyocytes was determined by Western blotting. An increase in the level of membrane Grb-2 and caveolin-3 was observed following ischemic preconditioning as compared to control cells. The formation of this 30 Kd-betaDG degradation product is potentially related to the transition from the reversible to the irreversible phase of myocardial ischemic cell injury and a decrease in 30 Kd-betaDG might mediate the cardioprotection provided by ischemic preconditioning.
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PMID:An ischemic beta-dystroglycan (betaDG) degradation product: correlation with irreversible injury in adult rabbit cardiomyocytes. 1261 68

Aquaporins (AQPs) are a family of water channel proteins that assist in maintenance of the cellular osmotic environment and whole body fluid balance. Specialized organ-specific AQPs are important in physiologic and pathologic processes but little is known about AQPs in the human heart. AQP1 has been identified in rodent heart. We investigated the presence and localization of AQP1 in human heart and skeletal muscle using immunohistochemistry and confocal microscopy, western blot and reverse transcriptase-polymerase chain reaction. There was abundant AQP1 present in both cardiac and skeletal muscle. Immunohistochemistry revealed co-localization of AQP1 with vinculin, a t-tubule marker, and caveolin-3. No novel sequences bearing an NPA box motif common to other AQPs were identified in human heart using degenerative PCR analysis. We conclude that AQP1 is present in the human heart. AQP1 co-localizes with t-tubular and caveolar proteins. Cardiac AQPs may have a role during osmotic stresses including ischemia/reperfusion and cardiopulmonary bypass.
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PMID:Expression of aquaporin 1 in human cardiac and skeletal muscle. 1513 60

Mechanisms underlying gender differences in cardiovascular disease are poorly understood. We found previously that, under hypercontractile conditions, female hearts exhibit significantly less ischemia/reperfusion injury than males. Here we show that male wild-type (WT) mouse hearts pretreated with 10 nmol/L isoproterenol before ischemia exhibited increased injury versus female hearts, but this relative protection in females was absent in eNOS(-/-) and nNOS(-/-) hearts. In isoproterenol-treated female versus male hearts, there was also more endothelial NO synthase (eNOS) associated with cardiomyocyte caveolin-3, and more neuronal NOS (nNOS) translocation to caveolin-3 during ischemia/reperfusion. S-nitrosothiol (SNO) formation was increased in isoproterenol-treated ischemic/reperfused hearts in all mouse genotypes, but only in WT mice was SNO content significantly higher in females than males. Using the biotin switch method, we identified the L-type Ca2+ channel alpha1 subunit as the predominant S-nitrosylated protein in membrane fractions, and following isoproterenol and ischemia/reperfusion male/female differences in SNO were seen only in WT hearts, but not in constitutive NOS(-/-) genotypes. The isoproterenol-induced increase in L-type Ca2+ current (ICa) was smaller in females versus in males, but NOS blockade increased ICa in females. This gender difference in ICa in isoproterenol-treated myocytes (and abolition on NOS inhibition) was mirrored exactly in Ca2+ transients and SR Ca2+ contents. In conclusion, these data suggest that eNOS and nNOS both play roles in the gender differences observed in ischemia/reperfusion injury under adrenergic stimulation, and also demonstrate increased S-nitrosylation of the L-type Ca2+ channels in female cardiomyocytes.
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PMID:Hypercontractile female hearts exhibit increased S-nitrosylation of the L-type Ca2+ channel alpha1 subunit and reduced ischemia/reperfusion injury. 1648 23

The role of caveolae, membrane microenvironments enriched in signaling molecules, in myocardial ischemia is poorly defined. In the current study, we used cardiac myocytes prepared from adult rats to test the hypothesis that opioid receptors (OR), which are capable of producing cardiac protection in vivo, promote cardiac protection in cardiac myocytes in a caveolae-dependent manner. We determined protein expression and localization of delta-OR (DOR) using coimmunohistochemistry, caveolar fractionation, and immunoprecipitations. DOR colocalized in fractions with caveolin-3 (Cav-3), a structural component of caveolae in muscle cells, and could be immunoprecipitated by a Cav-3 antibody. Immunohistochemistry confirmed plasma membrane colocalization of DOR with Cav-3. Cardiac myocytes were subjected to simulated ischemia (2 h) or an ischemic preconditioning (IPC) protocol (10 min ischemia, 30 min recovery, 2 h ischemia) in the presence and absence of methyl-beta-cyclodextrin (MbetaCD, 2 mM), which binds cholesterol and disrupts caveolae. We also assessed the cardiac protective effects of SNC-121 (SNC), a selective DOR agonist, on cardiac myocytes with or without MbetaCD and MbetaCD preloaded with cholesterol. Ischemia, simulated by mineral oil layering to inhibit gas exchange, promoted cardiac myocyte cell death (trypan blue staining), a response blunted by SNC (37 +/- 3 vs. 59 +/- 3% dead cells in the presence and absence of 1 muM SNC, respectively, P < 0.01) or by use of the IPC protocol (35 +/- 4 vs. 62 +/- 3% dead cells, P < 0.01). MbetaCD treatment, which disrupted caveolae (as detected by electron microscopy), fully attenuated the protective effects of IPC or SNC, resulting in cell death comparable to that of the ischemic group. By contrast, SNC-induced protection was not abrogated in cells incubated with cholesterol-saturated MbetaCD, which maintained caveolae structure and function. These findings suggest a key role for caveolae, perhaps through enrichment of signaling molecules, in contributing to protection of cardiac myocytes from ischemic damage.
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PMID:Protection of adult rat cardiac myocytes from ischemic cell death: role of caveolar microdomains and delta-opioid receptors. 1650 Oct 18

Ischemia-reperfusion activates ERK and p38 MAPK in cardiac membranes, but the role of caveolae in MAPK signaling during this stress has not been studied. The purpose of this study was to determine the effect of in vivo myocardial ischemia-reperfusion on the level and distribution of caveolin-1 and -3 and cholesterol as well as MAPK activation in caveolin-enriched fractions. Adult male rats were subjected to in vivo regional myocardial ischemia induced by 25 min of coronary artery occlusion and 10 min (n = 5) or 2 h (n = 4) of reperfusion. Another group of rats served as appropriate nonischemic time controls (n = 4). A discontinuous sucrose density gradient was used to isolate caveolae/lipid rafts from ischemic and nonischemic heart tissue. Caveolin-1 and -3, as well as cholesterol, were enriched in the light fractions. A redistribution of caveolin-3 and a reduction in caveolin-1 and cholesterol levels in the light fractions occurred after 10 min of reperfusion. The ERKs were activated in ischemic zone light and heavy fractions by 10 min of reperfusion. p44 ERK was activated after 2 h of reperfusion only in the light fractions, whereas p42 ERK phosphorylation was increased in the light and heavy fractions. Although no p38 MAPK activation occurred after 10 min of reperfusion, 2 h of reperfusion caused significant activation of p38 MAPK in nonischemic zone light and heavy fractions. These results show the importance of caveolar membrane/lipid rafts in MAPK signaling and suggest that subcellular compartmentation of p44/p42 ERKs and p38 MAPK may play distinct roles in the response to myocardial ischemia-reperfusion.
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PMID:Regional myocardial ischemia-induced activation of MAPKs is associated with subcellular redistribution of caveolin and cholesterol. 1656 1

Sphingomyelin breakdown product ceramide has recently been found to induce an adaptive response and reduce myocardial ischemia/reperfusion injury. Since activation of MAP kinases plays an essential role in myocardial adaptation to ischemic stress and since ceramide is involved in lipid raft formation where MAP kinases can be translocated in response to stress, we reasoned that preconditioning may potentiate the translocation of MAP kinases into the lipid raft. To test the hypothesis, rats were divided into five groups: (i) control, (ii) ischemia/reperfusion (I/R), (iii) I/R+C-2 ceramide, (iv) adapted and (v) adapted+desipramine, an inhibitor of ceramide formation. Isolated hearts were preperfused for 15 min with Krebs Henseleit bicarbonate (KHB) buffer in the absence or presence of 10 microM desipramine followed by adaptation induced by four cyclic episodes of 5 min ischemia and 10 min reperfusion. For myocardial adaptation to ischemia with ceramide, the hearts were perfused with 1 microM C-2 ceramide. All hearts were then subjected to 30 min ischemia and 2 h of reperfusion. As expected, both ischemic adaptation and ceramide adaptation made the heart resistant to I/R injury as evidenced by improved ventricular performance and reduced myocardial infarct size and cardiomyocyte apoptosis, which were significantly blocked with desipramine indicating the involvement of ceramide in ischemic adaptation. Ceramide also participated in the formation of lipid raft, and desipramine disrupted the raft formation. In the adapted hearts, there was an increased association of the proapoptotic p38MAPKalpha with caveolin-1 while there was a reduced association of anti-apoptotic p38MAPKbeta with caveolin-3 indicating reduced amount of p38MAPKalpha and increased amount of p38MAPKbeta were available to the adapted hearts thereby generating a survival signal. Desipramine decreased the association of P38MAPKalpha and C-2 ceramide increased the association of P38MAPKalpha with the lipid raft. The survival signal was further confirmed by increased phosphorylation of AKT and enhanced induction of expression of Bcl-2 during adaptation and its reversal with desipramine. The results indicated a unique ceramide signaling the ischemic and PC hearts involving lipid rafts, which generated a survival signal by differentially associating the p38MAPKalpha and p38MAPKbeta with the caveolin-1 and caveoli-3, respectively.
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PMID:Generation of survival signal by differential interaction of p38MAPKalpha and p38MAPKbeta with caveolin-1 and caveolin-3 in the adapted heart. 1706 50

Volatile anesthetics protect the heart from ischemia/reperfusion injury but the mechanisms for this protection are poorly understood. Caveolae, sarcolemmal invaginations, and caveolins, scaffolding proteins in caveolae, localize molecules involved in cardiac protection. We tested the hypothesis that caveolae and caveolins are essential for volatile anesthetic-induced cardiac protection using cardiac myocytes (CMs) from adult rats and in vivo studies in caveolin-3 knockout mice (Cav-3(-/-)). We incubated CM with methyl-beta-cyclodextrin (MbetaCD) or colchicine to disrupt caveolae formation, and then exposed the myocytes to the volatile anesthetic isoflurane (30 min, 1.4%), followed by simulated ischemia/reperfusion (SI/R). Isoflurane protected CM from SI/R [23.2+/-1.6% vs. 71.0+/-5.8% cell death (assessed by trypan blue exclusion), P<0.001] but this protection was abolished by MbetaCD or colchicine (84.9+/-5.5% and 64.5+/-6.1% cell death, P<0.001). Membrane fractionation by sucrose density gradient centrifugation of CM treated with MbetaCD or colchicine revealed that buoyant (caveolae-enriched) fractions had decreased phosphocaveolin-1 and caveolin-3 compared to control CM. Cardiac protection in vivo was assessed by measurement of infarct size relative to the area at risk and cardiac troponin levels. Isoflurane-induced a reduction in infarct size and cardiac troponin relative to control (infarct size: 26.5%+/-2.6% vs. 45.3%+/-5.4%, P<0.01; troponin: 27.7+/-4.4 vs. 77.7+/-11.8 ng/ml, P<0.05). Isoflurane-induced cardiac protection was abolished in Cav-3(-/-) mice (infarct size: 53.4%+/-6.1% vs. 53.2%+/-3.5%, P<0.01; troponin: 102.1+/-22.3 vs. 105.9+/-8.2 ng/ml, P<0.01). Isoflurane-induced cardiac protection is thus dependent on the presence of caveolae and the expression of caveolin-3. We conclude that caveolae and caveolin-3 are critical for volatile anesthetic-induced protection of the heart from ischemia/reperfusion injury.
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PMID:Caveolin-3 expression and caveolae are required for isoflurane-induced cardiac protection from hypoxia and ischemia/reperfusion injury. 1805 55

Lipid rafts represent a subcompartment of the plasma membrane that coordinate and regulate varieties of signaling processes while caveolins are the integral membrane protein of the lipid raft. To study the role of lipid raft in ischemic preconditioning (PC) of the heart, rat hearts were perfused by working mode and then preconditioned in absence or presence of a lipid raft disintegrator, Methyl-beta-cyclodextrin. As expected, precondition made the heart resistant to ischemia reperfusion (I/R) injury as evident by improved ventricular performance, reduced myocardial infract size and cardiomyocyte apoptosis. Cyclodextrin abolished the cardioprotection. Transmission Electron Microscopy revealed severe degeneration, swelling of mitochondria, chromatin condensation and myofibril disarray in cyclodextrin treated PC heart similar to I/R heart. In the PC hearts, there was an increased association of the proapoptotic p38MAPKalpha with caveolin-1 while there was a reduced association of anti-apoptotic p38MAPKbeta with caveolin-3 indicating that reduced amount of p38MAPKalpha and increased amount of p38MAPKbeta were available to the adapted hearts thereby generating a survival signal. In contrast, there was very weak caveolin-MAP kinase interaction in cyclodextrin treated heart. Myocardial damage was further confirmed by reduced or no expression of anti-apoptotic phospho-AKT, Bcl2, Bcl-xl and increased expression of pro-apoptotic JNK, BAX, and p53 in methyl-beta-cyclodextrin (lipid raft disintegrator) treated heart. These results indicate that lipid raft play a pivotal role in the generation of survival signal in PC or adapted heart and disintegration of lipid raft completely abolish cardioprotection.
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PMID:Essential role of lipid raft in ischemic preconditioning. 1844 21

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