Endothelin in coronary endothelial dysfunction early after human heart transplantation

Weis, Michael; Wildhirt, Stephen M.; Schulze, C.; Rieder, Gabriele; Wilbert-Lampen, Ute; Wolf, W; Arendt, R; Enders, G.; Meiser, Bruno; Scheidt, Wolfgang von

doi:10.1016/s1053-2498(99)00081-9

Cited by 37 publications

(22 citation statements)

References 34 publications

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“…Our data corroborate the relationship between heightened perioperative levels of ET-1 and early myocardial dysfunction. In addition, ET-1 has been suggested to play a role in late CAV, and reduced overall survival [25][26][27][28] in clinical cardiac transplantation. ET-1 antagonists improve systolic function in animal models of cardiac transplantation.…”

Section: Discussionmentioning

confidence: 99%

Heart Preservation Using Continuous Ex Vivo Perfusion Improves Viability and Functional Recovery

Ozeki

Kwon

et al. 2007

Circ J

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Section: Discussionmentioning

confidence: 99%

Heart Preservation Using Continuous Ex Vivo Perfusion Improves Viability and Functional Recovery

Ozeki

Kwon

et al. 2007

Circ J

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“…3,[7][8][9][10] Endothelial dysfunction is implicated in the development of coronary vasospasm, unstable angina, myocardial infarction, atherosclerosis, and transplant coronary disease. 4,6,8,13,14,19 The normally functioning endothelium maintains ET-1 and NO in balance.…”

Section: Discussionmentioning

confidence: 99%

“…7 Several investigators have demonstrated that ET-1 adversely affects endothelial function as well as outcomes after cardiac surgery. 3,[7][8][9][10] We have previously shown that ET-1 results in endothelial dysfunction after cardiac transplantation and antagonism with Bosentan abrogated this effect. 9 Previous investigators have demonstrated that ET-1 modulates endothelial nitric oxide synthase (eNOS) expression as well as NO production.…”

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confidence: 99%

Elevated Endothelin-1 Levels Impair Nitric Oxide Homeostasis Through a PKC-Dependent Pathway

et al. 2006

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Background-Endothelin-1 (ET-1) plays an important role in the maintenance of vascular tone and pathological states such as ischemia/reperfusion (I/R) injury, coronary vasospasm, and cardiac allograft vasculopathy. We assessed the effects of elevated ET-1 levels as seen after I/R to determine if ET-1 modulates nitric oxide (NO) production via the translocation of specific protein kinase C (PKC) isoforms. Methods and Results-Human saphenous vein endothelial cells (HSVECs) (nϭ8) were incubated with ET-1 or phosphate-buffered saline (PBS) for 24 hours. NO production was determined in the supernatant by measuring nitrate/nitrite levels. Protein expression of endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), caveolin-1 and PKC were determined. Lastly, PKC translocation and activity were assessed after exposure to the drug of interest. HSVECs exposed to ET-1 displayed decreased NO production. PKC inhibition reduced NO production, whereas PKC activation increased production. NO production was maintained when HSVECs exposed to ET-1 were treated with the PKC agonist, PMA. eNOS protein expression was reduced after ET-1 treatment. PKC inhibition also downregulated eNOS protein expression, whereas PMA upregulated expression. ET-1 exposure led to a significant increase in PKC␦ and PKC translocation compared with control, whereas translocation of PKC was inhibited. ET-1 exposure significantly reduced overall PKC activity compared with control. Conclusions-Our study demonstrates that high levels of ET-1 impair endothelial NO production via an isoform-specific PKC-mediated inhibition of eNOS expression. ET-1 antagonism with bosentan stimulates translocation of PKC and leads to increased PKC activity and NO production. ET-1 antagonism may provide a novel therapeutic strategy to improve vascular homeostasis.

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“…43 Epicardial and microvascular endothelium-dependent and -independent vasomotor dysfunction are frequently observed after HTx. 44 Coronary allograft endothelial dysfunction is associated with circulating endothelin levels, 45 enhanced graft cytokine activation, 46 and CMV infection, 47 whereas statin treatment reduces the progression of epicardial and microvascular dysfunction. 48 Coronary endothelial dysfunction predicts the development of intimal thickening 49 and predicts cardiovascular end points after HTx.…”

Section: Detection Of Coronary Vasomotor Alterationsmentioning

confidence: 99%

Cardiac Allograft Vasculopathy

2008

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Abstract-Cardiac allograft vasculopathy (CAV) continues to limit the long-term success of cardiac transplantation.Recent insights have underscored the fact that innate and adaptive immune responses are involved in the pathogenesis of CAV. Vascular lesions are the result of cumulative endothelial injuries induced both by alloimmune responses and by nonspecific insults (including ischemia-reperfusion injury, viral infections, and metabolic disorders) in the context of impaired repair mechanisms. Intravascular ultrasound is the most sensitive method for detection of CAV, and progressive intimal thickening in the first posttransplant year identifies patients at high risk for future cardiovascular events. Encouraging results with regard to the detection of CAV by noninvasive methods should be an incentive to apply routine noninvasive imaging during mid-to long-term follow-up. Improved immunosuppressive drugs, including mycophenolate mofetil and proliferation signal inhibitors, as well as statins (in part via immunomodulation), have beneficial effects on CAV progression, although there is still a need to confirm the impact of vasodilators in improving outcome after heart transplantation. Coronary revascularization for CAV is only palliative, with no long-term survival benefit. Three main strategies for CAV prevention are currently under investigation: inhibition of growth factors and cytokines, cell therapy, and tolerance induction. However, because individual responses to an allograft change over time, assays to monitor the recipient's immune response and individualized methods for therapeutic immune modulation are clearly needed. (Circulation. 2008;117:2131-2141.)

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Endothelin in coronary endothelial dysfunction early after human heart transplantation

Cited by 37 publications

References 34 publications

Heart Preservation Using Continuous Ex Vivo Perfusion Improves Viability and Functional Recovery

Heart Preservation Using Continuous Ex Vivo Perfusion Improves Viability and Functional Recovery

Elevated Endothelin-1 Levels Impair Nitric Oxide Homeostasis Through a PKC-Dependent Pathway

Cardiac Allograft Vasculopathy

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