FTY720 prevents progression of renal fibrosis by inhibiting renal microvasculature endothelial dysfunction in a rat model of chronic kidney disease
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Endothelial Dysfunction
Blood urea nitrogen
Peritubular capillaries
Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible NOS (iNOS), and cyclooxygenase-2 (COX2) in the rat. Inhibiting COX2 abolished the ATV-induced IS limitation without affecting p-eNOS and iNOS expression. We investigated 1) whether 3-day ATV pretreatment limits IS in eNOS(-/-) and iNOS(-/-) mice and 2) whether COX2 expression and/or activation by ATV is eNOS, iNOS, and/or NF-kappaB dependent. Male C57BL/6 wild-type (WT), University of North Carolina eNOS(-/-) and iNOS(-/-) mice received ATV (10 mg.kg(-1).day(-1); ATV(+)) or water alone (ATV(-)) for 3 days. Mice underwent 30 min of coronary artery occlusion and 4 h of reperfusion, or hearts were harvested and subjected to ELISA, immunoblotting, biotin switch, and electrophoretic mobility shift assay. As a result, ATV reduced IS only in the WT mice. ATV increased eNOS, p-eNOS, iNOS, and COX2 levels and activated NF-kappaB in WT mice. It also increased myocardial COX2 activity. In eNOS(-/-) mice, ATV increased COX2 expression but not COX2 activity or iNOS expression. NF-kappaB was not activated by ATV in the eNOS(-/-) mice. In the iNOS(-/-) mice, eNOS and p-eNOS levels were increased but not iNOS and COX2 levels; however, NF-kappaB was activated. In conclusion, both eNOS and iNOS are essential for the IS-limiting effect of ATV. The expression of COX2 by ATV is iNOS, but not eNOS or NF-kappaB, dependent. Activation of COX2 is dependent on iNOS.
Endothelial NOS
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Zhihong Yang, MD and Xiu-Fen Ming, MD, PhD Zhihong Yang, MD, Department of Medicine, Division of Physiology, University of Fribourg, Rue du Musée 5, CH-1700 Fribourg, Switzerland Xiu-Fen Ming, MD, PhD, Department of Medicine, Division of Physiology, University of Fribourg, Rue du Musée 5, CH-1700 Fribourg, Switzerland Reprint Requests: Prof. Zhihong Yang, MD, Vascular Biology Laboratory, Department of Medicine, Division of Physiology, University of Fribourg, Rue du Musée 5, CH-1700 Fribourg, Switzerland, Tel: 41-26-300 85 93; Fax: 41-26-300 96 36; Email: zhihong.yang{at}unifr.ch
Endothelial Dysfunction
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The vascular endothelium expresses endothelial nitric oxide synthase (eNOS) that generates nitric oxide (NO) to help maintain vascular integrity due to its anti-inflammatory, antiproliferative, and antithrombogenic effects. Pharmacological blockade of NO production has been shown to exacerbate renal injury in chronic renal disease and induces endothelial cell loss. However, pharmacological inhibition of NO nonspecifically blocks other types of NOS and therefore does not define the specific role of eNOS in kidney disease. We hypothesized that a lack of endothelial eNOS can induce a loss of glomerular and peritubular capillary endothelium and exacerbate renal injury in progressive renal disease. We tested out this hypothesis using remnant kidney (RK) in eNOS knockout (eNOS KO) mice. Systolic blood pressure was significantly higher, and renal function was worse in RK-eNOS KO mice compared with those in RK-C57BL6 mice. eNOS deficiency resulted in more severe glomerulosclerosis, mesangiolysis, and tubular damage. Glomerular and tubular macrophage infiltration and collagen deposition were also greater in RK-eNOS KO mice. Renal injuries in the RK-eNOS KO mice were accompanied by a greater loss of endothelial cells that was shown to be due to both a decrease in endothelial cell proliferation and an increase in apoptosis. A lack of eNOS accelerates both glomerular and tubulointerstitial injury with a loss of glomerular capillaries and peritubular capillaries. Impaired endothelial function is likely a direct risk factor for renal disease.
Peritubular capillaries
Glomerulosclerosis
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Previous studies have demonstrated that the polyphenolic compound, reseveratrol (RSV), from the skin of red grapes increases endothelial nitric oxide synthase (eNOS) activity. However, the mechanism by which RSV increases eNOS activity is unknown. Therefore, we have investigated changes in eNOS phosphorylation at Ser1179, Ser635, Thr495 as well as changes in eNOS association with Hsp90, Akt, and cdc37 in bovine aortic endothelial cells (BAECs) treated with varying doses of RSV for 0, 20, 60 min as well as 72 h. Acute RSV treatment (less than 1) resulted in no significant ( P >0.05) changes in eNOS phosphorylation or changes in eNOS association with Hsp90, Akt or cdc37. In contrast, 72h treatment of BAECs at higher concentrations of RSV significantly ( P <0.05) increased eNOS phosphorylation and protein association that was consistent with the increase in eNOS expression. In conclusion, these data suggest that RSV‐induced eNOS activity is primarily due to increased eNOS expression and that acute (less than 1 h) RSV treatment does not alter post‐translational eNOS regulatory mechanisms. Supported by AHA SDG 0430157N (MBH) and William & Mary HHMI Undergraduate Research Program Student Grant (KNS)
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Objectives: Advancing age is characterized with the development of vascular endothelial dysfunction which is the major risk factor for the development of cardiovascular diseases. TRPA1 is involved in lifespan and its agonist cinnameldehyde(CA)mediates endothelial vasorelaxation. Therefore, we hypothesized that TRPA1 is involved in aging-related endothelial dysfunction and CA administration would improve endothelial function. Methods: Human umbilical vein endothelial cells (HUVECs) were cultured until 14th passage and the 6th passage were used as control. Twenty-four months-old male Sprague Dawley (SD) rats were given dietary CA (0.2%) and six months-old rodents were used as young control. Rodent carotid arteries vasorelaxation was detected by wire myograph. TRPA1, Nrf2, UCP2 and its target genes as well as eNOS, p-eNOS were analysed by immunoblotting. Results: Immunoblotting and immunofluorescence confirmed the TRPA1 expression in HUVECs and vascular endothelium. CA(10 μM) promoted Nrf2 nuclear translocation and eNOS phosphorylation, led to the up-regulation of HO-1, GPx-1, NQO-1 and a reduction in ROS production in HUVECs. However, these effects of CA could be reversed by TRPA1 antagonist, HC030031 (10 μM), Nrf2 inhibitor brusatol (40 nM) or UCP2 inhibitor. NO level was found decreased, and enthdothelium dependent relaxation was impaired in carotid arteries of aged rats, but both improved after 12 weeks of CA administration. Immunoblotting showed the expression of TRAP1, Nrf2, UCP2 and p-eNOS significantly decreased in vascular tissue of aged rats but partly restored after CA treatment. Conclusion: TRPA1 may be involved in aging related endothelial dysfunction and CA improved endothelial dependent vasorelaxation through Nrf2 activation as a TRPA1 agonist.
Endothelial Dysfunction
Myograph
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Aim To investigate the interaction between regulatory proteins related to the activation of eNOS and CYP4A/20-HETE.Methods The endothelia of pulmonary artery of new born bovine were cultured and divided into four groups: controlling group: ethanol solvent as vehicle (the volume is the same with 1×10~ -6 mol·L~ -1 20-HETE) was added to culture dish and incubated for 10 min; 20-HETE 5 min treatment group:1×10~ -6 mol·L~ -1 20-HETE was added to culture dish and incubated for 5 min; 20-HETE 10 min treatment group:1×10~ -6 mol·L~ -1 20-HETE was added to culture dish and incubated for 10 min; VEGF 10 min treatment group: 1×10~ -8 mol·L~ -1 VEGF was added to culture dish and incubated for 10 min. CYP4A,eNOS and proteins related to the activation of eNOS were measured by Immunoprecipitating and immunobloting.Results Expressions of eNOS and phospho-eNOS(Ser1177)in PAECs were upregulated after the cells were treated with 20-HETE, and similar phenomena were observed when 20-HETE was replaced by VEGF; 20-HETE increased the binding of Hsp、Akt and eNOS.Conclusions ①20-HETE phosphorylates eNOS at Ser1177 site which activates the eNOS to catalyze L-aginine to produce nitric oxide.②eNOS binds with Hsp90 and Akt in endothelial cell of pulmonary artery and 20-HETE increase the binding. ③eNOS binds with CYP4A in endothelial cell of pulmonary artery.
Endothelial NOS
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Two strains of endothelial nitric oxide synthase (eNOS)-deficient (−/−) mice have been developed that respond differently to myocardial ischemia-reperfusion (MI/R). We evaluated both strains of eNOS −/− mice in an in vivo model of MI/R. Harvard (Har) eNOS −/− mice ( n = 12) experienced an 84% increase in myocardial necrosis compared with wild-type controls ( P < 0.05). University of North Carolina (UNC) eNOS −/− ( n = 10) exhibited a 52% reduction in myocardial injury versus wild-type controls ( P < 0.05). PCR analysis of myocardial inducible NO synthase (iNOS) mRNA levels revealed a significant ( P < 0.05) increase in the UNC eNOS −/− mice compared with wild-type mice, and there was no significant difference between the Har eNOS −/− and wild-type mice. UNC eNOS −/− mice treated with an iNOS inhibitor (1400W) exacerbated the extent of myocardial necrosis. When treated with 1400W, Har eNOS −/− did not exhibit a significant increase in myocardial necrosis. These data demonstrate that two distinct strains of eNOS −/− mice display opposite responses to MI/R. Although the protection seen in the UNC eNOS −/− mouse may result from compensatory increases in iNOS, other genes may be involved.
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Objective To study the mechanism of homocysteine(Hcy) on eNOS activity in human umbilical vein endothelial cells(HUVECs).Methods HUVECs were collected and cultured.Then the second passage of HUVECs were cultured with different Hcy concentrations for different times.The expression of HSP90,Akt,caveolin-1,eNOS,P-eNOS proteins were detected by Western blot and the expression of Caveolin-1,eNOS,DDAH mRNA by RT-PCR.Results Compared with control group,both in base and calcium ionophore activated state,the expression of Caveolin-1 group increased obviously(P0.05) in concentration and time-dependent manner,but the expression of Akt showed decreasing(P0.05).The expression of eNOS did not change significantly.There was no difference in the expression of HSP90,eNOS,P-eNOS protein and mRNA among every group.DDAH mRNA among every group too.Conclusions There was no relationship between decreasing activity of eNOS induced by Hcy and eNOS expression,Hcy probably can increase the association of Caveolin-1 and eNOS by enhancing the expression of Caveolin-1,and reduce the complex formation of Caveolin-1,Akt,Caveolin-1 in HUVEC both in base and activated state,which can decrease the activity of eNOS.
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