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)

OPC-28326, 4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl) piperidine hydrochloride monohydrate, is a newly developed selective peripheral vasodilator and increases blood flow to lower extremities with alpha2-adrenergic antagonist property. Here, we investigated the effect of OPC-28326 on ischemia-induced angiogenesis. OPC-28326 enhanced tube formation by human aortic endothelial cells (HAECs). Moreover, OPC-28326 enhanced the number of microvessels sprouting from aortic rings embedded in collagen gel. OPC-28326 markedly induced phosphorylation of endothelial nitric oxide synthase (eNOS) in HAECs via phosphatidylinositol-3 kinase PI3K/Akt (PI3K/Akt) pathway. Next, the angiogenic effect of OPC-28326 was evaluated in a mouse hindlimb ischemia model. Blood flow recovery to the ischemic leg was significantly enhanced by OPC-28326. Furthermore, anti-CD31 immunostaining revealed that OPC-28326 increased capillary density in the ischemic muscle. However, OPC-28326 failed to promote blood flow recovery in ischemic hindlimb in eNOS-deficient mice. These results suggest that OPC-28326 promotes angiogenesis, which was associated with activation of eNOS via PI3K/Akt pathway. OPC-28326 might be promising to treat patients with ischemic vascular diseases.
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PMID:OPC-28326, a selective femoral arterial vasodilator, augments ischemia induced angiogenesis. 1722 8

Cell therapy is a promising option for the treatment of ischemic diseases. Infusion or injection of stem or progenitor cells has improved neovascularization and heart function after ischemia in various experimental studies and clinical phase II and III trials. One potential limitation for cell therapy is a low rate of engraftment and persistence of cells in the ischemic tissue. Moreover, impairment of the number and function of patient-derived progenitor cells might limit the efficiency of autologous stem cell therapy. Therefore, strategies to augment cell function, survival, and homing could be crucial to improve success rates for cell therapy. Experimental studies have provided novel options for improving survival and function by transduction of stem or progenitor cells with prosurvival genes (e.g. Akt or telomerase). Pretreatment of cells with small molecules, such as statins, p38 inhibitors, or endothelial nitric oxide synthase enhancers, has been used to augment cell homing, integration, and functional recovery after induction of ischemia. Priming of the tissue by mechanical activation or application of growth factors might further improve recruitment and incorporation of cells. In this article we summarize the experimental studies providing novel concepts for cell-enhancement strategies to aid the treatment of peripheral artery occlusive and ischemic heart disease.
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PMID:Cell-enhancement strategies for the treatment of ischemic heart disease. 1723 Feb 7

Reactive oxygen species (ROS) generated during ischemia-reperfusion (I/R) enhance myocardial injury, but brief periods of myocardial ischemia followed by reperfusion [ischemic preconditioning (IP)] induce cardioprotection. Ischemia is reported to stimulate glucose uptake through the translocation of GLUT-4 from the intracellular vesicles to the sarcolemma. In the present study we demonstrated involvement of ROS in IP-mediated GLUT-4 translocation along with increased expression of caveolin (Cav)-3, phospho (p)-endothelial nitric oxide synthase (eNOS), p-Akt, and decreased expression of Cav-1. The rats were divided into the following groups: 1) control sham, 2) N-acetyl-L-cysteine (NAC, free radical scavenger) sham (NS), 3) I/R, 4) IP + I/R (IP), and 5) NAC + IP (IPN). IP was performed by four cycles of 4 min of ischemia and 4 min of reperfusion followed by 30 min of ischemia and 3, 24, 48 h of reperfusion, depending on the protocol. Increased mRNA expression of GLUT-4 and Cav-3 was observed after 3 h of reperfusion in the IP group compared with other groups. IP increased expression of GLUT-4, Cav-3, and p-AKT and p-eNOS compared with I/R. Coimmunoprecipitation demonstrated decreased association of Cav-1/eNOS in the IP group compared with the I/R group. Significant GLUT-4 and Cav-3 association was also observed in the IP group. This association was disrupted when NAC was used in conjunction with IP. It clearly documents a significant role of ROS signaling in Akt/eNOS/Cav-3-mediated GLUT-4 translocation and association in IP myocardium. In conclusion, we demonstrated a novel redox mechanism in IP-induced eNOS and GLUT-4 translocation and the role of caveolar paradox in making the heart euglycemic during the process of ischemia, leading to myocardial protection in a clinically relevant rat ischemic model.
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PMID:Redox regulation of ischemic preconditioning is mediated by the differential activation of caveolins and their association with eNOS and GLUT-4. 1727 24

Caveolins (Cav), the principal structural proteins of the caveolar domains, have been implicated in the pathogenesis of ischemic injury. Indeed, changes in caveolin expression and localization have been reported in renal and myocardial ischemia. Genetic ablation of the Cav-1 gene in mice was further shown to increase the extent of ischemic injury in a model of hindlimb ischemia. However, the role of Cav-1 in the pathogenesis of cerebral ischemia remains unknown. Immunoblot and immunofluorescence analyses of rat brains subjected to middle cerebral artery occlusion revealed marked increases in endothelial Cav-1 and Cav-2 protein levels. To directly assess the functional role of caveolins in the pathogenesis of cerebral ischemic injury, we next investigated the effects of cerebral ischemia in caveolin knockout (KO) mice. Interestingly, Cav-1 KO mice showed a marked increase of cerebral volume of infarction, as compared with wild-type and Cav-2 KO mice. Immunofluorescence analyses showed an increased number of proliferating endothelial cells in wild-type ischemic brains, as compared with Cav-1 KO ischemic brains. Immunoblot analyses of wild-type ischemic brains showed an increase in endothelial nitric oxide synthase protein levels. Conversely, the protein levels of endothelial nitric oxide synthase remained unchanged in Cav-1 KO ischemic brains. TUNEL analysis also showed increased apoptotic cell death in Cav-1 KO ischemic brains, as compared with wild-type ischemic brains. Our findings indicate cerebral ischemia induces a marked increase in endothelial Cav-1 and Cav-2 protein levels. Importantly, genetic ablation of the Cav-1 gene in mice results in increased cerebral volume of infarction. Mechanistically, Cav-1 KO ischemic brains showed impaired angiogenesis and increased apoptotic cell death.
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PMID:Caveolin-1 deficiency increases cerebral ischemic injury. 1729 79

Rho-kinase has been identified as one of the effectors of the small GTP-binding protein Rho. Accumulating evidence has demonstrated that the Rho/Rho-kinase pathway plays an important role in various cellular functions, not only in vascular smooth muscle cell (VSMC) contraction but also in VSMC proliferation, cell migration, and gene expression. Two isoforms of Rho-kinase encoded by two different genes have been identified: ROCK1 and ROCK2. These isoforms are ubiquitously expressed, but with preferential expression of ROCK2 in the brain and skeletal muscle. The expression of Rho-kinase itself is mediated by the protein kinase C/NF-kappaB pathway with an inhibitory and stimulatory modulation by estrogen and nicotine, respectively. At the cellular level, Rho-kinase mediates VSMC contraction, stimulates VSMC proliferation and migration, and enhances inflammatory cell motility. Rho-kinase also upregulates various molecules that accelerate inflammation/oxidative stress, thrombus formation, and fibrosis, while it downregulates endothelial nitric oxide synthase and inhibits insulin signaling. Rho-kinase activity regulates major morphogenetic events during embryonic development through cell migration, differentiation, and axis formation. In animal and clinical studies, Rho-kinase has been shown to be substantially involved in the pathogenesis of vasospasm, arteriosclerosis, hypertension, pulmonary hypertension, and ischemia/reperfusion injury. Fasudil, a selective Rho-kinase inhibitor developed in Japan, is effective for the treatment of a wide range of cardiovascular diseases, with reasonable safety. Thus Rho-kinase is an important therapeutic target in cardiovascular medicine. This review summarizes the recent progress in the study of Rho-kinase and addresses future perspectives of Rho-kinase inhibitors.
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PMID:Progress of the study of rho-kinase and future perspective of the inhibitor. 1732 36

Erythropoietin (EPO) has been proposed as a novel cytoprotectant in ischemia-reperfusion (I/R) injury of the brain, heart, and kidney. However, whether EPO exerts its protection by prevention of postischemic microcirculatory deterioration is unknown. We have investigated the effect of EPO on I/R-induced microcirculatory dysfunctions. We used the mouse dorsal skinfold chamber preparation to study nutritive microcirculation and leukocyte-endothelial cell interaction in striated muscle of the dorsal skinfold by in vivo fluorescence microscopy before 3 h of ischemia and during 5 days of reperfusion. Animals were pretreated with EPO (5,000 U/kg body wt) 1 or 24 h before ischemia. Vehicle-treated I/R-injured animals served as controls. Additional animals underwent sham operation only or were pretreated with EPO but not subjected to I/R. I/R significantly (P < 0.05) reduced functional capillary density, increased microvascular permeability, and enhanced venular leukocyte-endothelial cell interaction during early reperfusion. These findings were associated with pronounced (P < 0.05) arteriolar constriction and diminution of blood flow during late reperfusion. Pretreatment with EPO induced EPO receptor and endothelial nitric oxide synthase expression at 6 h of reperfusion (P < 0.05). In parallel, EPO significantly (P < 0.05) reduced capillary perfusion failure and microvascular hyperpermeability during early reperfusion and arteriolar constriction and flow during late reperfusion. EPO pretreatment substantially (P < 0.05) diminished I/R-induced leukocytic inflammation by reducing the number of rolling and firmly adhering leukocytes in postcapillary venules. EPO applied 1 h before ischemia induced angiogenic budding and sprouting at 1 and 3 days of reperfusion and formation of new capillary networks at 5 days of reperfusion. Thus our study demonstrates for the first time that EPO effectively attenuates I/R injury by preserving nutritive perfusion, reducing leukocytic inflammation, and inducing new vessel formation.
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PMID:Human recombinant erythropoietin protects the striated muscle microcirculation of the dorsal skinfold from postischemic injury in mice. 1733 94

The aim of this study was to investigate the protective effect of ibuprofen on testicular torsion/detorsion-induced ischemia/reperfusion (I/R) injury. A total of 48 prepubertal male Wistar albino rats were divided into two models: early and late orchiectomy. Testicular torsion was created by rotating the right testis 720 degrees in a clockwise direction. The ischemia period was 5 h and orchiectomy was performed after 5 h of detorsion in the early orchiectomy model (EOM). In the late orchiectomy model (LOM), the ischemia period was 5 h and orchiectomy was performed after 7 days of detorsion. In the EOM, ibuprofen (70 mg/kg, po) was administrated only once, 40 min prior to detorsion. In the LOM, ibuprofen (70 mg/kg, po) was administered 40 min before detorsion, once daily for 7 days. Bilateral orchiectomy was performed in all groups to measure the tissue levels of malondialdehyde (MDA) and to microscopically investigate light and electrons. The presence of endothelial nitric oxide synthase (eNOS) activity was shown with immunohistochemical studies. Spermatogenesis and mean seminiferous tubule diameter (MSTD) were significantly decreased in ipsilateral and contralateral testis when both early and late I/R groups were compared to the sham groups. Furthermore, ibuprofen-treated animals showed an improved histological appearance in both models of testicular torsion. Ibuprofen treatment prevented lipid peroxidation resulting in decreased MDA accumulation in the testes of both models. After I/R, eNOS immunoreactivity was increased in the testicular tissues. Ibuprofen treatment decreased eNOS immunoreactivity in the germ cells of the tubules in the contralateral testes, but intense eNOS immunoreactivity was shown in the ipsilateral testes of the LOM. Electron microscopy of the testes of rats demonstrated that ibuprofen pretreatment was particularly effective in preventing the mitochondrial degeneration in both Sertoli and spermatid cells in the LOM. Because of its anti-inflammatory and antioxidant effects, ibuprofen pretreatment may have protective effects in the experimental testicular torsion/detorsion model in rats.
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PMID:Protective effects of ibuprofen on testicular torsion/detorsion-induced ischemia/reperfusion injury in rats. 1734 63

Akt is expected to be an effective target for the treatment of ischemia-reperfusion injury (I/R) due to its anti-apoptotic properties and its ability to activate the endothelial nitric oxide synthase (eNOS) enzyme. Therefore, this study was aimed to determine the efficacy of an active mutant of Akt (myr-Akt) to decrease I/R injury in a model of orthotopic liver transplantation in pigs. In addition, we analyzed the contribution of nitric oxide in the Akt-mediated effects by using an eNOS mutant (S1179DeNOS) that mimics the phosphorylation promoted by Akt in the eNOS sequence. Donors were treated with adenoviruses codifying for myr-Akt, S1179DeNOS or beta-galactosidase 24 h before liver harvesting. Then, liver grafts were orthotopically transplanted into their corresponding recipients. Levels of transaminases and lactate dehydrogenase (LDH) increased in all recipients after 24 h of transplant. However, transaminases and LDH levels were significantly lower in the myr-Akt group compared with vehicle. The percentage of apoptotic cells and the amount of activated-caspase 3 protein were also markedly reduced in myr-Akt-treated grafts after 4 days of liver transplant compared with vehicle and S1179DeNOS groups. In conclusion, myr-Akt gene therapy effectively exerts cytoprotection against hepatic I/R injury regardless of the Akt-dependent eNOS activation.
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PMID:Gene transduction of an active mutant of akt exerts cytoprotection and reduces graft injury after liver transplantation. 1739 Nov 22

Microsphere embolism-induced up-regulation of endothelial nitric oxide synthase (eNOS) in endothelial cells of brain microvessels was found after brain ischemia. The eNOS induction preceded disruption of the blood-brain barrier following ischemia. In vascular endothelial cells, microsphere embolism-induced eNOS expression was associated with protein tyrosine nitration, which is a marker of generation of peroxynitrite. To determine whether eNOS expression and protein tyrosine nitration in vascular endothelial cells mediates the blood-brain barrier disruption in the microsphere embolism brain, we tested the effect of a novel calmodulin-dependent NOS inhibitor, DY-9760e, which inhibits eNOS activity and in turn protein tyrosine nitration. Concomitant with inhibition of protein tyrosine nitration in vascular endothelial cells, DY-9760e significantly inhibited BBB disruption as assessed by Evans blue excretion. DY-9760e also inhibited cleavage of poly(ADP-ribose) polymerase as a marker of the apoptotic pathway in vascular endothelial cells. Taken together with previous evidence in which DY-9760e inhibited brain edema, microsphere embolism-induced eNOS expression in vascular endothelial cells likely mediates BBB disruption and in turn brain edema.
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PMID:[Brain embolism-induced injury of vascular endothelial cells and a novel vasoprotective drug]. 1740 6

The vascular endothelium of the coronary arteries has been identified as the important organ that locally regulates coronary perfusion and cardiac function by paracrine secretion of nitric oxide (NO) and vasoactive peptides. NO is constitutively produced in endothelial cells by endothelial nitric oxide synthase (eNOS). NO derived from this enzyme exerts important biological functions including vasodilatation, scavenging of superoxide and inhibition of platelet aggregation. Routine cardiac surgery or cardiologic interventions lead to a serious temporary or persistent disturbance in NO homeostasis. The clinical consequences are "endothelial dysfunction", leading to "myocardial dysfunction": no- or low-reflow phenomenon and temporary reduction of myocardial pump function. Uncoupling of eNOS (one electron transfer to molecular oxygen, the second substrate of eNOS) during ischemia-reperfusion due to diminished availability of L-arginine and/or tetrahydrobiopterin is even discussed as one major source of superoxide formation. Therefore maintenance of normal NO homeostasis seems to be an important factor protecting from ischemia/reperfusion (I/R) injury. Both, the clinical situations of cardioplegic arrest as well as hypothermic cardioplegic storage are followed by reperfusion. However, the presently used cardioplegic solutions to arrest and/or store the heart, thereby reducing myocardial oxygen consumption and metabolism, are designed to preserve myocytes mainly and not endothelial cells. This review will focus on possible drug additives to cardioplegia, which may help to maintain normal NO homeostasis after I/R.
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PMID:Nitric oxide homeostasis as a target for drug additives to cardioplegia. 1748 42


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