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)

Ischemic postconditioning (Postcond) is defined as rapid intermittent interruptions of blood flow in the early phase of reperfusion and mechanically alters the hydrodynamics of reperfusion. Although Postcond has been demonstrated to attenuate ischemia/reperfusion (I/R) injury in the heart and brain, its roles to renal I/R injury remain to be defined. In the present study, we examined the role of Postcond in I/R injury in a right-nephrectomized rat model. Postcond prevents the renal dysfunction and cell apoptosis induced by I/R and increases nitric oxide (NO) release and renal NO synthase (endothelial, eNOS and inducible, iNOS) expression. In contrast, enhancement of endothelin-1 (ET-1) in the kidney after the reperfusion was markedly suppressed by Postcond. These findings indicate that Postcond can inhibit renal I/R injury. The protective effect of Postcond is closely related to the NO production following the increase in eNOS and iNOS expression and the suppressive effect of ET-1 overproduction.
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PMID:Attenuation of reperfusion injury by renal ischemic postconditioning: the role of NO. 1754 62

Mobilization and recruitment of bone marrow-derived progenitor cells (BMDPCs) play an important role in postischemic tissue repair. Patients with coronary artery disease (CAD) or peripheral vascular disease (PVD) exhibit endothelial dysfunction, and as a result are likely to have a reduced number of progenitor cells mobilized in their peripheral circulation following ischemic injury. Identification of eNOS independent pathways for BMDPC mobilization may have important therapeutic value in this patient population. To identify such mechanisms we investigated the effect of granulocyte-colony stimulating factor (GCSF) and stem cell factor (SCF) in eNOS-KO mice with and without surgical hind-limb ischemia. Our results suggest that BMDPC mobilization can be achieved via activation of NO-independent pathways.
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PMID:Role of endothelial nitric oxide in bone marrow-derived progenitor cell mobilization. 1755 3

To investigate the involvement of reperfusion-induced salvage kinases (RISK) as possible signaling molecules for the cardioprotective effects of BMS-180448, a prototype mitochondrial ATP-sensitive K+ (mitoK(ATP)) channel opener, we measured its cardioprotective effects in a rat model of ischemia/reperfusion (I/R) heart injury, together with western blotting analysis of five different signaling proteins. In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, BMS-180448 (1, 3 and 10 microM) significantly increased reperfusion left ventricular developed pressure (LVDP) and 30-min reperfusion double product (heart rate x LVDP) in a concentration-dependent manner, while decreasing left ventricular end-diastolic pressure (LVEDP) throughout reperfusion period in a concentration-dependent manner. SDS-PAGE/western blotting analysis of left ventricle reperfused for 30 min revealed that BMS-180448 significantly decreased phospho-GSK3beta at high concentration, whereas it tended to increase slightly phospho-eNOS and phospho-p70S6K with concentration. However, BMS-180448 had no effect on phospho-Akt and phospho-Bad. These results suggest that the cardioprotective effects of BMS-180448 against I/R heart injury may result from direct activation of mitoK(ATP) channel in cardiomyocytes, with the minimal role of RISK pathway in the activation of this channel and the cardioprotective effects of BMS-180448.
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PMID:Cardioprotective effects of BMS-180448, a prototype mitoK(ATP) channel opener, and the role of salvage kinases, in the rat model of global ischemia and reperfusion heart injury. 1761 84

Moderate consumption of red wine is associated with a decreased incidence of cardiovascular diseases in populations with relatively high amount of fat in the diet. However, the mechanisms involved in this protective effect are not completely understood. Here we show that moderate consumption of red wine (equivalent to 2 glasses/day in humans) but not ethanol only, improves blood flow recovery by 32% after hindlimb ischemia in hypercholesterolemic ApoE-deficient mice. In ischemic tissues, red wine consumption reduces oxidative stress and increases capillary density by 46%. Endothelial progenitor cells (EPCs) have been shown to have an important role in postnatal neovascularization. We found that the number of EPCs is increased by 60% in ApoE mice exposed to red wine. Moreover, the migratory capacity of EPCs is significantly improved in red wine-drinking mice. The wine used in our study is a cabernet sauvignon from Languedoc-Roussillon, France, which contains a relatively high concentration (4-6 mg/L) of the polyphenolic antioxidant resveratrol. We demonstrate that resveratrol can rescue oxidized low-density lipoprotein (oxLDL)-induced impairment of in vitro angiogenic activities in human umbilical vein endothelial cells (HUVECs). Resveratrol exposure is also associated with increased activation of Akt/eNOS together with a restoration of nitric oxide production in HUVECs exposed to oxLDL. Our study suggests that moderate consumption of red wine improves ischemia-induced neovascularization in high-cholesterol conditions by increasing the number and the functional activities of EPCs and by restoring the Akt-eNOS-NO pathway.
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PMID:Moderate consumption of red wine (cabernet sauvignon) improves ischemia-induced neovascularization in ApoE-deficient mice: effect on endothelial progenitor cells and nitric oxide. 1764 Nov 50

Excessive oxidative stress has been implicated in the pathology and complications of diabetes, which leads to myocardial ischemia reperfusion injury. The present study was designed to examine whether resveratrol (trans-3,5,4'-trihydroxystilbene), a polyphenolic compound present in red wine has a direct cardioprotective effect on diabetic myocardium. Resveratrol (2.5 mg/kg body wt/day) and L-NAME (25 mg/kg body wt/day) were administered orally for 15 days to streptozotocin (65 mg/kg)-induced diabetic rats. Sprague Dawley rats were divided into 5 groups: (i) control, (ii) diabetic, (iii) diabetic+resveratrol, (iv) diabetic+resveratrol+L-NAME (nitric oxide synthase inhibitor), and (v) diabetic+L-NAME. In our present study resveratrol demonstrated significant reduction in glucose level in diabetic rats. After the treatment, the hearts were excised and subjected to 30 min of global ischemia followed by 2 h of reperfusion. Resveratrol-treated diabetic rats demonstrated significant reduction in glucose levels as compared to the nontreated diabetic animals, and improved left ventricular function throughout reperfusion compared to the diabetic or L-NAME-treated animals (dp/dt(max) 1457+/-51 vs 999+/-44 mm Hg/s at 120 min reperfusion). Cardioprotection from ischemic injury in resveratrol-treated diabetic rats showed decreased infarct size (42% vs 51%) and cardiomyocyte apoptosis (35% vs 40%) as compared with diabetic animals. Resveratrol produced significant induction of p-AKT, p-eNOS, Trx-1, HO-1, and VEGF in addition to increased activation of MnSOD activity in diabetic animals compared to nondiabetic animals. However treatment with L-NAME in resveratrol-treated and nontreated diabetic animals demonstrated significant downregulation of the above-noted protein expression profile and MnSOD activity. In the present study we found that the mechanism(s) responsible for the cardioprotective effect of resveratrol in the diabetic myocardium include upregulation of Trx-1, NO/HO-1, and VEGF in addition to increased MnSOD activity and reduced blood glucose level. Thus this study shows a novel mechanism of pharmacological preconditioning with resveratrol in the diabetic myocardium.
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PMID:Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: Role of nitric oxide, thioredoxin, and heme oxygenase. 1766 36

Sphingosine 1-phosphate (S1P), a multifunctional lipid mediator that signals via the S1P family of G protein-coupled receptors (S1PR), regulates vascular maturation, permeability, and angiogenesis. In this study, we explored the role of S1P 2 receptor (S1P2R) in normal vascularization and hypoxia-triggered pathological angiogenesis of the mouse retina. S1P2R is strongly induced in ECs during hypoxic stress. When neonatal mice were subjected to ischemia-driven retinopathy, pathologic neovascularization in the vitreous chamber was suppressed in S1p2-/- mice concomitant with reduction in endothelial gaps and inflammatory cell infiltration. In addition, EC patterning and normal revascularization into the avascular zones of the retina were augmented. Reduced expression of the proinflammatory enzyme cyclooxygenase-2 (COX-2) and increased expression of eNOS were observed in the S1p2-/- mouse retina. S1P2R activation in ECs induced COX-2 expression and suppressed the expression of eNOS. These data identify the S1P2R-driven inflammatory process as an important molecular event in pathological retinal angiogenesis. We propose that antagonism of the S1P2R may be a novel therapeutic approach for the prevention and/or treatment of pathologic ocular neovascularization.
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PMID:Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina. 1771 Feb 32

We studied the endothelial nitric oxide synthase (eNOS or NOS-3) gene as a potential modifier of the cerebral response to ischemia by investigating the association of two common polymorphisms with ischemic stroke volume. We genotyped an intronic variable number tandem repeat and a single nucleotide polymorphism, G894T, in 132 patients with nonlacunar ischemic strokes in whom clinical data and stroke lesion volume were recorded. Our results show that all genotypes are in Hardy-Weinberg equilibrium. After adjustment of covariates, neither of the NOS-3 polymorphisms showed significant differences comparing the genotypes and mean stroke volume (analysis of variance). Our results do not suggest a major gene effect of the NOS-3 gene as a modifier of the cerebral response to ischemia.
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PMID:Analysis of the endothelial nitric oxide synthase gene as a modifier of the cerebral response to ischemia. 1790 64

To investigate the effects of phosphodiesterase (PDE) 5 inhibitors, sildenafil citrate and vardenafil HCl, on testicular germ cell apoptosis and also on the expressions of eNOS and iNOS within the bilateral testis after a unilateral torsion in a rat model. Forty-eight Wistar Albino rats, weighing between 210 and 262 g, were housed in individual cages. The rats were randomly assigned into four main groups and each group received drugs. Saline, sildenafil citrate and vardenafil HCl were given to each for 1 month and the last received no drug. After 1 month, testicular torsion was created for 1 h of ischemia and the left testis was untwisted and replaced to the scrotum for 2 h of reperfusion. At the end of 3 h, contralateral and ipsilateral testes were removed for histopathologic and biochemical examinations. Under light microscopy; the histopathological patterns of the contralateral testes in all groups were not affected. Mean apoptotic cell, eNOS and iNOS levels were increased in saline study group. The rats treated with vardenafil and sildenafil (groups 2s and 3s) showed significantly increased apoptotic cell, eNOS and iNOS values in ipsilateral testis (P < 0.05). Sildenafil citrate and vardenafil HCl caused an exaggerated testicular apoptosis after IR injury in rats. Additionally these drugs increased the NOSs levels in the testicular tissue.
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PMID:Effect of phospodiesterase 5 inhibitors on apoptosis and nitric oxide synthases in testis torsion: an experimental study. 1798 35

Hypercholesterolemia (HC) induced endothelial cell dysfunction and decreased endothelial nitric oxide formation results in impaired angiogenesis and subsequent cardiovascular disorders. Therapeutic angiogenesis is known to be a novel strategy for treatment of patients with ischemic heart disease. We have shown that secoisolariciresinol diglucoside (SDG) is angiogenic as well as cardioprotective against myocardial ischemia. In the present study, we examined the efficacy of SDG in a hypercholesterolemic myocardial infarction (MI) model. The rats were maintained on a normal and high cholesterol diet (2%) for 8 weeks followed by oral administration of SDG (20 mg/kg) for 2 weeks. The rats were divided into four groups (n=24 in each): Control (C); SDG control (SDG); HC; and HC+SDG (HSDG). Isolated hearts subjected to 30 min of global ischemia followed by 120 min of reperfusion were used to measure the cardiac functions, infarct size and to examine the protein expression profile. After treatment, MI was induced by ligating the left anterior descending artery. Echocardiographic parameters were examined 30 days after MI. Significant reduction in total cholesterol, LDL-cholesterol, triglycerides and an increase in HDL-cholesterol levels were observed in HSDG as compared to the HC. Decreased infarct size was observed in the HSDG group (43%) compared to the HC (54%). Increased phosphorylation of endothelial nitric oxide synthase (p-eNOS) (3.1-fold), vascular endothelial growth factor (1.9-fold) and heme oxygenase-1 (2.3-fold) was observed in the HSDG group as compared to the HC group. Significant improvement in left ventricular functions was also observed in the HSDG group as evidenced by increased ejection fraction (55% vs. 45%), fractional shortening (28% vs. 22%) and decreased left ventricular inner diameter in systole (8 vs. 6 mm) in HSDG compared to HC. Moreover, MI model has shown increased capillary density (2531 vs. 1901) and arteriolar density (2.6 vs. 1.8) in SDG-treated rats as compared to the HC. The increased capillary and arteriolar density along with increased left ventricular functions on SDG treatment might be due to increased HO-1, VEGF and p-eNOS expression. In conclusion, our study demonstrates for the first time that SDG treatment reduces ventricular remodeling by neovascularization of the infarcted HC myocardium.
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PMID:Secoisolariciresinol diglucoside induces neovascularization-mediated cardioprotection against ischemia-reperfusion injury in hypercholesterolemic myocardium. 1800 68

Prostanoids are cyclic lipid mediators which arise from enzymic cyclooxygenation of linear polyunsaturated fatty acids, e.g. arachidonic acid (20:4 n 6, AA). Biologically active prostanoids deriving from AA include stable prostaglandins (PGs), e.g. PGE(2), PGF(2alpha), PGD(2), PGJ(2) as well as labile prostanoids, i.e. PG endoperoxides (PGG(2), PGH(2)), thromboxane A(2) (TXA(2)) and prostacyclin (PGI(2)). A "Rabbit aorta Contracting Substance" (RCS) played important role in discovering of labile PGs. RCS was discovered in the Vane's Cascade as a labile product released along with PGs from the activated lung or spleen. RCS was identified as a mixture of PG endoperoxides and thromboxane A(2). Stable PGs regulate the cell cycle, smooth muscle tone and various secretory functions; they also modulate inflammatory and immune reactions. PG endoperoxides are intermediates in biosynthesis of all prostanoids. Thromboxane A(2) (TXA(2)) is the most labile prostanoid (with a half life of 30 s at 37 degrees C). It is generated mainly by blood platelets. TXA(2) is endowed with powerful vasoconstrictor, cytotoxic and thrombogenic properties. Again the Vane's Cascade was behind the discovery of prostacyclin (PGI(2)) with a half life of 4 min at 37 degrees C. It is produced by the vascular wall (predominantly by the endothelium) and it acts as a physiological antagonist of TXA(2). Moreover, prostacyclin per se is a powerful cytoprotective agent that exerts its action through activation of adenylate cyclase, followed by an intracellular accumulation of cyclic-AMP in various types of cells. In that respect PGI(2) collaborates with the system consisting of NO synthase (eNOS)/nitric oxide free radical (NO)/guanylate cyclase/cyclic-GMP. Both cyclic nucleotides (c-AMP and c-GMP) act in synergy as two energetic fists which defend the cellular machinery from being destroyed by endogenous or exogenous aggressors. Recently, a new partner has been recognized in this endogenous defensive squadron, i.e. a system consisting of heme oxygenase (HO-1)/carbon monoxide (CO)/biliverdin/biliverdin reductase/bilirubin. The expanding knowledge on the pharmacological steering of this enzymic triad (PGI(2)-S/eNOS/HO-1) is likely to contribute to the rational therapy of many systemic diseases such as atherosclerosis, diabetes mellitus, arterial hypertension or Alzheimer diseases. The discovery of prostacyclin broadened our pathophysiological horizon, and by itself opened new therapeutic possibilities. Prostacyclin sodium salt and its synthetic stable analogues (iloprost, beraprost, treprostinil, epoprostenol, cicaprost) are useful drugs for the treatment of the advanced critical limb ischemia, e.g. in the course of Buerger's disease, and also for the treatment of pulmonary artery hypertension (PAH). In this last case a synergism between prostacyclin analogues and sildenafil (a selective phosphodiesterase 5 inhibitor) or bosentan (an endothelin ET-1 receptor antagonist) points our to complex mechanisms controlling pulmonary circulation. At the Jagiellonian University we have demonstrated that several well recognised cardiovascular drugs, e.g. ACE inhibitors (ACE-I), statins, some of beta-adrenergic receptor antagonists, e.g. carvedilol or nebivolol, anti-platelet thienopyridines (ticlopidine, clopidogrel) and a metabolite of vitamin PP--N(1)-methyl-nicotinamide--all of them are endowed with the in vivo PGI(2)-releasing properties. In this way, the foundations for the Endothelial Pharmacology were laid.
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PMID:Prostacyclin among prostanoids. 1827 80


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