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Elena B Okon

Publications and source records attributed to Elena B Okon.

9 recordsLinked to original sources
PubMed2006

Reduced expression of vascular endothelial growth factor paralleled with the increased angiostatin expression resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in human type 2 diabetic arterial vasculature.

Impaired angiogenesis could contribute to the increased incidence of coronary and peripheral artery disease in diabetic patients. Angiogenesis is initiated by vascular endothelial growth factor (VEGF), a potent angiogenic cytokine, and suppressed by angiostatin, which is generated by matrix metalloproteinase (MMP)-2 and -9 through proteolytic cleavage of plasminogen. We hypothesized that MMP-2 and -9 were upregulated in the diabetic vasculature, resulting in increased angiostatin production and reduced blood vessel formation. In diabetic internal mammary artery samples (n=32) collected from patients undergoing coronary artery bypass grafting surgery, capillary density was only 30% of that in the nondiabetic vessels (n=32), whereas VEGF expression was reduced by 48%. Diabetes upregulated the expression and the gelatinolytic activity of MMP-2 and -9. Active MMP-2 and -9 were released from diabetic arteries, but not from nondiabetic vessels, during phenylephrine-induced vasoconstriction. Diabetes enhanced transcription and protein expression of tissue inhibitor of MMP (TIMP)-1 but had an opposite effect on TIMP-2. In diabetic vessels angiostatin was increased by 62% and was positively correlated with the activities of MMP-2 and -9 (r2=0.806 and 0.742, respectively). This report indicated a strong correlation between the upregulation of MMP-2 and MMP-9 and the increased angiostatin expression in the human diabetic arterial vasculature. The enhanced angiostatin production with a reduced VEGF formation may explain the pathogenesis of impaired angiogenesis in diabetes mellitus.

Aged↗
PubMed2006

Pharmacologic relaxation of vein grafts is beneficial compared with pressure distention caused by upregulation of endothelial nitric oxide synthase and nitric oxide production.

OBJECTIVE: Pressure distention of veins during preparation for bypass surgery is believed to impair vascular integrity and reduce graft patency. We previously suggested a combination of pharmacologic vasodilatators as an alternative to distention. Vascular homeostasis is largely regulated by nitric oxide. We investigated the role of distention in comparison with pharmacologic vasorelaxation in the regulation of nitric oxide synthases, nitric oxide bioavailability, and vascular reactivity in vein grafts. METHODS: In a porcine model the internal jugular vein from either side received pressure distention or the combination of vasodilators (alpha-adrenergic antagonist, phenoxybenzamine, 10 micromol/L; Rho-kinase inhibitor, HA-1077 [fasudil], 50 mumol/L; calcium blocker, nicardipine, 1 micromol/L) and then was grafted into the carotid artery. Regulation of nitric oxide synthase, as well as nitrate and nitrite levels, were examined in vein grafts after 2 weeks of implantation. RESULTS: Distention of jugular veins resulted in reduction of vasoconstriction in response to depolarization and agonist stimulation. Arterial grafting doubled inducible nitric oxide synthase expression in both grafts but caused a pronounced upregulation of endothelial nitric oxide synthase protein (by 57.3% +/- 5%) only in drug-treated grafts, whereas in distended grafts the endothelial nitric oxide synthase level was decreased by 27.5% +/- 2.7%. The downregulated endothelial nitric oxide synthase level in the distended grafts was accompanied by a 45.2% +/- 3.1% reduction of phospho-endothelial nitric oxide synthase Ser1177 levels and by a significant reduction in nitric oxide synthase activity (12.1% +/- 1.2%) and nitrate production (48.9% +/- 5.6%) in comparison with that seen in drug-treated grafts. CONCLUSIONS: Pharmacologic preparation of the vein grafts results in upregulation of endothelial nitric oxide synthase and increased nitric oxide production in the vein grafts after arterial implantation. This might provide greater clinical benefit than conventional pressure-distention methods.

Animals↗
PubMed2006

Fast, cheap and out of control: a zero curation model for ontology development.

During two days at a conference focused on circulatory and respiratory health, 68 volunteers untrained in knowledge engineering participated in an experimental knowledge capture exercise. These volunteers created a shared vocabulary of 661 terms, linking these terms to each other and to a pre-existing upper ontology by adding 245 hyponym relationships and 340 synonym relationships. While ontology-building has proved to be an expensive and labor-intensive process using most existing methodologies, the rudimentary ontology constructed in this study was composed in only two days at a cost of only 3 t-shirts, 4 coffee mugs, and one chocolate moose. The protocol used to create and evaluate this ontology involved a targeted, web-based interface. The design and implementation of this protocol is discussed along with quantitative and qualitative assessments of the constructed ontology.

Artificial Intelligence↗
PubMed2005

Pressure distention compared with pharmacologic relaxation in vein grafting upregulates matrix metalloproteinase-2 and -9.

OBJECTIVE: Autogenous vein bypasses are a common and effective method to treat occlusive disease. During surgical preparation, veins are routinely pressure distended to overcome vasospasm and twists. Distention, however, is believed to promote vascular remodeling and contribute to decreased graft patency. Pharmacologic vasorelaxation with a combination of effective vasodilators has been suggested as an alternative to pressure distention. The extracellular matrix (ECM)-degrading matrix metalloproteinases (MMPs) have been implicated in vascular remodeling and neointima formation. The purpose of the present study was to compare the effects of pressure distention with pharmacologic vasorelaxation on graft remodeling and regulation of MMP-2 and MMP-9 in porcine vein grafts. METHODS: Carotid artery bypass utilizing internal jugular veins was performed in eight female white pigs. Jugular veins were randomized to receive pressure distention (300 mm Hg for 2 minutes) or a combination of vasodilators (the alpha-adrenergic antagonist phenoxybenzamine, 10 micromol/L; the Rho-kinase inhibitor HA-1077 [fasudil], 50 micromol/L; and the calcium-channel blocker nicardipine, 1 micromol/L) for 30 minutes and then were grafted into the carotid arteries. Two weeks after surgery, vein graft samples were analyzed for vessel intimal and medial area, lumen diameter, and ECM composition. Molecular analysis using reverse transcription-polymerase chain reaction, Western immunoblotting, gelatin zymography, and reverse zymography were performed to study the expression and activation of MMP-2 and MMP-9, and tissue inhibitors of MMP (TIMP)-1 and TIMP-2. RESULTS: Pressure distention irreversibly overstretched the porcine jugular vein and increased MMP-2 and MMP-9 proteolytic activity by 40% and 77%, respectively. Two weeks of vein grafting in the carotid arterial bed induced vessel wall thickening, ECM modification, and neointima formation, which were more pronounced in the distended grafts (P < .05) and accompanied by an increase in MMP expression and activity. Distended grafts demonstrated higher percentages of active MMP-9 (17.8% +/- 1.0%) and higher activities of latent (35.5% +/- 3.3%) and active MMP-2 (69.6% +/- 8.8%) than the pharmacologically treated grafts. Protein expression of TIMP-1 and TIMP-2 was downregulated after arterial grafting, but the pharmacologically treated grafts expressed significantly more TIMP-1 protein (by 36.8% +/- 4.1%) than the distended ones. The activities of TIMPs were markedly decreased after grafting, contributing to the upregulated MMP activity. CONCLUSIONS: Pressure distention of vein grafts before implantation, compared with pharmacologic vasodilatation, stimulates neointima formation and augments MMP activities. Pharmacologic vasorelaxation may be clinically superior to distention in attenuating graft remodeling and possibly improving graft patency. CLINICAL RELEVANCE: Autogenous vein bypasses are a common and effective method to treat occlusive disease. This study demonstrated that pressure distention, a common preparatory procedure in bypass surgery, upregulates extracellular matrix-degrading matrix metalloproteinases, which predisposes vein grafts to extensive remodeling and contributes to neointima formation and graft occlusion. The topical application of a combination of vasodilators to the vein graft before implantation may be clinically superior to pressure distention in attenuating graft remodeling and may possibly improve graft patency and reduce secondary surgical interventions.

Animals↗
PubMed2005

Compromised arterial function in human type 2 diabetic patients.

Diabetes is associated with a perturbation of signaling pathways in vascular tissue, which causes vasomotor dysfunction such as hypertension and accelerated atherosclerosis. In the present study, the mechanisms of vasomotor dysfunction, Akt (Thr308 and Ser473) phosphorylation and expression of endothelial NO (nitric oxide) synthase, and inducible NO synthase were investigated in human diabetic internal mammary arteries. The phospho-Akt (Thr308) level in arteries from diabetic patients was reduced to about one-half of the level in nondiabetic patients, suggesting impaired insulin signaling in human diabetic vascular tissue. Augmented vasoconstriction was observed in diabetic arteries, due in part to deficiency of basal and stimulated NO production. This correlated with decreased endothelial NO synthase expression and activity in diabetic vessels. The sensitivity of diabetic vessels to the NO donor, sodium nitroprusside, was reduced as well, suggesting that NO breakdown and/or decreased sensitivity of smooth muscle to NO are also responsible for abnormal vasoconstriction. In addition, the abnormal vasoconstriction in diabetic vessels was not completely abolished in the presence of Nomega-nitro-L-arginine methyl ester, revealing that NO-independent mechanisms also contribute to vasomotor dysfunction in diabetes. In conclusion, diabetes downregulates the Akt-signaling pathway and compromises human arterial function through a decrease in NO availability as well as through NO-independent mechanisms.

Adult↗
PubMed2004

Effect of moderate pressure distention on the human saphenous vein vasomotor function.

BACKGROUND: Manual pressure distension, which is commonly applied to the human saphenous vein graft for coronary artery bypass, is believed to have detrimental consequences for the graft patency. The vasomotor function of the vein after distention during surgical preparation for grafting and after distention in laboratory conditions at pressure of 50 to 600 mm Hg was studied. The effect of a combination of vasodilative agents to prevent vasospasm was also tested. METHODS: The contractile and dilatory responses of distended and undistended human saphenous veins and those after drug treatment were examined in organ baths under isometric conditions. RESULTS: Distention at the pressure range 100 to 300 mm Hg resulted in an increased contractile response of the saphenous vein to both alpha-adrenergic activation with 50 micromol/L phenylephrine (153.73% +/- 15.69%) and depolarization with 80 mmol/L K(+) (141.03% +/- 15.13%) in comparison with the undistended vein and did not impair the relaxation. In contrast manual distention during surgical preparation abolished the contractile response and impaired the relaxation. The application of a combination of vasodilative drugs (alpha-adrenergic antagonist phenoxybenzamine, 10 micromol/L, Rho-kinase inhibitor HA-1077, 50 micromol/L, and calcium blocker nicardipine, 1 micromol/L) eliminated the contractile response of the vein to phenylephrine and 80 mmol/L K(+). This effect was sustained more than 20 hours after the washout of the drugs. CONCLUSIONS: The distention of the human saphenous vein at moderate pressure combined with the application of the effective combination of vasodilative drugs before grafting into the arterial circulation could be a beneficial alternative to the current practice of uncontrolled pressure distension.

Adult↗
PubMed2003

Augmented contractile response of vascular smooth muscle in a diabetic mouse model.

The vasomotor properties of isolated aortae and mesenteric arteries of insulin-resistant ob/ob and 57CBL/6J mice were compared in organ bath studies. Vessels from ob/ob mice were more sensitive to phenylephrine. Pretreatment with L-NAME caused similar leftward shifts of the phenylephrine concentration response curves in diabetic and non-diabetic vessels. The ob/ob aortae contracted in response to phenylephrine with roughly twice the force while they were not stiffer than control aortae. L-NAME caused a greater percentage increase in maximal force in the control than in the ob/ob tissue. Denudation potentiated force in the control aortae, but not in the ob/ob aortae. Endothelium-dependent relaxation in the ob/ob aortae and mesenteric arteries was impaired as manifested by a decreased sensitivity and maximal relaxation to acetylcholine, while the aortic basal eNOS mRNA levels did not differ between the two strains. In addition, ob/ob aortae were less sensitive to the nitric oxide donor sodium nitroprusside. Inhibition of endogenous prostaglandin synthesis with indomethacin (10 microM) partly normalized the contractile response of the ob/ob aortae and enhanced their endothelium-dependent relaxation. Neither blockade of endothelin-1 receptors (bosentan, 10 microM) nor PKC inhibition (calphostin, 1 microM) affected the contractile response to phenylephrine in the mouse aortae of either strain. In conclusion, vascular dysfunction in the aorta and mesenteric artery of ob/ob mice are due to increased smooth muscle contractility and impaired dilation but not to changes in elasticity of the vascular wall. Endothelium-produced prostaglandins contribute to the increased vasoconstriction.

Animals↗
PubMed2002

In the presence of L-NAME SERCA blockade induces endothelium-dependent contraction of mouse aorta through activation of smooth muscle prostaglandin H2/thromboxane A2 receptors.

1. The mechanism of transient contractions induced by the sarcoplasmic-endoplasmic reticulum calcium ATPase (SERCA) blocker cyclopiazonic acid (CPA) in the presence of L-NAME was investigated in mouse aorta. 2. The contractions elicited by 10 micro M CPA required an intact endothelium, were dependent upon external Ca(2+) and were prevented by 10 micro M indomethacin, the inhibitor of prostaglandin synthesis, or 1 micro M SQ29548, the specific prostaglandin H2/thromboxane A2 (PGH2/TXA2) receptor blocker. 3. A blocker of receptor/store operated Ca(2+) channels and voltage gated calcium channels (VGCC), SK&F 96365 (10 micro M), completely abolished the contractions, while a specific blocker of VGCC nifedipine (1 micro M) inhibited them by one third. 4. Dichlorobenzamyl hydrochloride, a blocker of Na(+)/Ca(2+) exchange effectively prevented return of tension to baseline value. 5. At higher concentrations (30-100 micro M) CPA induced indomethacin-resistant tonic contractions of mouse aorta. The CPA dose response curve for tonic contractions is shifted to the right compared to the transient contractions suggesting that smooth muscle is less sensitive to CPA than endothelium. 6. PGH2/TXA2 receptors in mouse aorta are highly sensitive to the thromboxane analogue U46619 (EC(50) : 1.93 nM). This compound stimulates contractions even in the absence of external Ca(2+), which are abolished by the Rho-kinase inhibitor HA-1077. 7. The results suggest that 10 micro M CPA induced capacitive Ca(2+) entry in endothelial cells stimulating the release of PGH2/TXA2, which subsequently caused smooth muscle contraction dependent on Ca(2+) influx and myofilament sensitization by Rho-kinase. Higher concentrations of CPA (30-100 micro M) directly induced contraction of mouse aortic smooth muscle.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗