Deamidated lipocalin-2 induces endothelial dysfunction and hypertension in dietary obese mice

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Endothelium-selective activation of AMP-activated protein kinase improves re-endothelialization and vascular function via induction of heme oxygenase-1 in diabetic mice

This journal suppl. entitled: EDHF 2012 - 10th Anniversary MeetingReduced number and impaired function of endothelial progenitor cells (EPCs) exacerbate vascular injury in diabetes. As AMP-activated kinase (AMPK) is a target of several anti-diabetic and cardiovascular drugs, this study investigated whether endothelium-selective activation of AMPK prevents diabetes-induced impairment in endothelial repair and vasoreactivity by impro...postprin

Elevated 20-Hete contributes to the improved endothelial function in lipocalin-2 deficient mice

This journal suppl. entitled: EDHF 2012 - 10th Anniversary MeetingLipocalin-2 is a glycoprotein constitutively secreted from adipocytes. In obese human subjects, the circulating lipocalin-2 level is elevated and positively correlated with systolic arterial blood pressure, dyslipidemia and insulin resistance. In mice, deficiency of lipocalin-2 protects against aging- and obesity-induced endothelial dysfunction and CYP4502C express...postprin

Dysfunction of the nitric oxide pathway during coronary endothelium regeneration | Dysfonction de la voie du monoxyde d'azote au cours de la régénération de l'endothélium coronarien.

Experiments were designed to determine whether or not aging per se or cellular density affects endothelial NO-synthase (eNOS) activity in cultured coronary endothelial cells of the pig. A diminished activity could explain the reduced endothelium-dependent relaxation to bradykinin previously observed during regeneration after endothelial injury. The results demonstrate that cell cultures derived from eight-day old regenerated endothelium exhibit a normal basal production of cyclic GMP, but a reduced response to bradykinin or the Ca2+ ionophore A23187. With multiple cellular passages, used to mimick aging, the basal production of cyclic GMP remained stable during the first passage, to decrease moderately after one month (4th passage). By contrast, the response to bradykinin was reduced as of the second passage, to remain stable thereafter. In cultured aortic endothelial cells, an increase in cellular density was accompanied by a reduced number of active eNOS-site, as well as a reduction of NO production in the response to both bradykinin and A23187. These results suggest that both the increased cellular density and cell senescence explain the endothelial dysfunction during regeneration. They permit a better understanding of the changes in vascular reactivity in the course of endothelial regeneration, and of its pathological consequences.link_to_subscribed_fulltex

Comparative study of coronary endothelial dysfunction after heart transplantation in domestic versus microswines

The present study was designed to compare the coronary endothelial dysfunction due to rejection and the development of accelerated atherosclerosis after heart transplantation in domestic (Large-White) versus microswines (Yucatan). A porcine model of heterotopic heart transplantation with preoperative immunologic typing of class I and II antigen of the major histocompatibility complex, permitting slow rejection without immunosuppression, was used to study these two end-points. The endothelium-dependent relaxations of allografted epicardial coronary arteries and native coronary arteries from domestic and microswines were compared 60 days after graft implantation using standard organ chamber experiments. There was a significant decrease of relaxations to serotonin and UK 14,304 (agonists coupled to Gi-proteins) and to sodium fluoride, a direct G-protein activator in both allografted coronary arteries from domestic and microswines. There was a significant increase in the prevalence of intimal thickening of allografted coronary arteries in both domestic and microswines. Domestic and microswines are useful animals for the study of coronary endothelial dysfunction and accelerated atherosclerosis after heart transplantation. Potential advantages of the microswines include ease of management for long-term use and chronic studies.link_to_subscribed_fulltex

Effect of intracoronary L-NAME infusion on endothelial dysfunction and intimal hyperplasia after heart transplantation

The present study was designed to examine the effect of nitric oxide synthase inhibition on coronary endothelial dysfunction and the development of accelerated atherosclerosis after heart transplantation. A porcine model was used to study the effect of inhibition of endothelial nitric oxide synthase by intracoronary L-Nitro Arginine Methyl Ester (L-NAME; 1 mg/kg/day) infusion by an osmotic pump on these two end-points. The endothelium-dependent relaxations of allografted epicardial coronary arteries, allografted arteries infused with L-NAME, allografted arteries mounted with the pump and vehicle and native coronary arteries were compared 30 days after graft implantation using standard organ chamber experiments. Intimai thickening was measured by light microscopy examination using a semiquantitative scale (0 to 4+ grading). There was a significant decrease of relaxations to serotonin in allografted arteries infused directly with L-NAME compared with allografted arteries from swines receiving the drug. There was a significant increase in the prevalence and severity of intimai thickening in allografted coronary arteries infused with L-NAME compared to allografts without infusion (prevalence: 100%, grade 3-4+ lesions 37.5%, and prevalence: 46.6%, grade 3-4 lesions: 0% respectively). Inhibition of the nitric oxide pathway accelerates the intimai thickening process leading to graft coronary vasculopathy.link_to_subscribed_fulltex

Inhibiting the NO pathway with intracoronary L-NAME infusion increases endothelial dysfunction and intimal hyperplasia after heart transplantation

Background: The endothelium protects the vascular wall through the nitric oxide (NO) release. Coronary endothelial dysfunction occurs early after heart transplantation and predicts the development of intimal thickening typical of graft coronary vasculopathy. Objective: We designed this study to examine the effect of endothelial NO synthase (eNOS) inhibition on the endothelial dysfunction caused by rejection and on the development of accelerated atherosclerosis after heart transplantation. Methods: To study the effect on these 2 end-points of inhibiting eNOS with intracoronary L-nitro arginine methyl ester (L-NAME; 1 mg/kg/day), infused with an osmotic pump for 30 days, we used a porcine model of heterotopic heart transplantation with pre-operative immunologic typing, to permit slow rejection without the need for immunosuppression. The endothelium-dependent relaxations of allografted coronary arteries, allografted arteries infused with L-NAME, allografted arteries mounted with the pump, and vehicle and native coronary arteries were compared 30 days after graft implantation using standard organ chamber experiments. We evaluated intimal thickening using a semi-quantitative scale (0-4+ grading). Results: A significant decrease in relaxations to serotonin (5-HT) occurred in allografted arteries infused directly with L-NAME compared with allografted arteries from swine receiving 5-HT, and relaxations in the latter were decreased compared with those of swine receiving the vehicle and native coronary arteries (p < 0.05). We found no significant differences in endothelium-dependent relaxations to bradykinin among coronary rings from all groups. We observed a significant increase in the prevalence and severity of intimal thickening in allografted coronary arteries infused with L-NAME compared with allografts not infused (p < 0.05), which had significantly more intimal thickening compared with native coronary arteries (p < 0.05). Conclusion: These results demonstrate that inhibiting the NO pathway worsens the endothelial dysfunction caused by rejection after heart transplantation and accelerates the intimal thickening process, leading to graft coronary vasculopathy. Strategies designed to preserve endothelial integrity and function of the endothelial NO pathway should be used to prevent graft coronary vasculopathy.link_to_subscribed_fulltex

Comparison of coronary endothelial dysfunction in the working and nonworking graft in porcine heterotopic heart transplantation

Background. The nonworking heterotopic heart transplantation model has been used extensively for the study of rejection and coronary endothelial function in different species. The effect of left ventricular loading in a working heart transplantation model, which may be associated with different coronary flow patterns and local nitric oxide release, on the development of coronary endothelial dysfunction and intimal hyperplasia, is unknown. Methods. Porcine retroperitoneal "nonworking" heterotopic transplantations (n=10) and "working" heart (with left ventricular filling) transplantations (n=7) were performed. The left ventricular pressure was 0±0 mm Hg and 91±11 mm Hg in the nonworking and working groups, respectively. In the latter, the left ventricle to systemic arterial pressure ratio was 0.76±0.08. Results. Sixty days after transplantation, epicardial coronary arteries from working and nonworking allografts developed a comparable selective endothelial dysfunction of Gi-protein mediated relaxations. There were no statistically significant differences in the prevalence of intimal hyperplasia, but the severity of intimal hyperplasia was significantly greater in allograft coronary arteries from the working hearts. Conclusion. Working heterotopic allografts develop an endothelial dysfunction comparable with that of nonworking allografts, which validates the use of the simpler nonworking graft for the study of endothelial function. The similar prevalence of intimal hyperplasia with the development of more severe coronary lesions in working hearts may be due to differences in local nitric oxide release in these two models.link_to_subscribed_fulltex

Time course of coronary endothelial dysfunction in acute untreated rejection after heterotopic heart transplantation

Background: Endothelial dysfunction is one of the early events leading to atherosclerosis. It occurs early after orthotopic heart transplantation and precedes the appearance of accelerated graft coronary artery disease believed to stem from chronic rejection of the endothelium. Acute rejection may contribute to the development of graft vasculopathy. Methods: To assess the time course and specific mechanisms of coronary endothelial dysfunction in acute untreated rejection, a swine model of retroperitoneal heterotopic heart transplantation was used. Large white swine (age 10 ± 2 weeks, weight 25 ± 5 kg) were serum-typed for class I antigen of the swine leukocyte antigen system and selected to ensure a similar degree of incompatibility. Donor hearts were preserved with normothermic blood cardioplegia and regional hypothermia; the mean ischemic time was 64 ± 15 minutes. Myocardial contractility decreased from day 5 (normal) to day 14 (weak), but electrical activity was preserved. All coronary arteries were patent, and International Society for Heart and Lung Transplantation grade 4 rejection was present in all hearts beyond 5 days. The endothelial function of epicardial coronary arterial rings of native and transplanted hearts was studied in organ chambers filled with modified Krebs-Ringer bicarbonate solution and compared 1, 5, 9, and 14 days after transplantation. Results: Maximal endothelium- independent relaxations were unaffected at all stages. Endothelium-dependent relaxations to serotonin and α2-adrenergic agonist UK 14304 (which activate receptors coupled to Gi-proteins) and to sodium fluoride (a direct G-protein activator) deteriorated progressively over time. At 14 days maximal relaxations to the calcium ionophore A23187, adenosine diphosphate, and bradykinin were also reduced, but to a lesser degree than those to serotonin and sodium fluoride. Histomorphometric studies of the allograft coronary artery rings showed progressive intimal hyperplasia from day 5 to day 14, with an increase in the incidence from 29% ± 8.3% to 61.5% ±12%. Conclusions: These studies show that endothelial dysfunction in untreated acute rejection after heart transplantation develops beyond 5 days and initially involves G-proteins; the dysfunction worsens over time to finally affect all endothelial mechanisms and vascular smooth muscle. The progression of the associated intimal hyperplasia parallels the alteration in endothelial function, suggesting a permissive role of the dysfunction in the development of this acute form of coronary graft vasculopathy.link_to_subscribed_fulltex