Selective improvement of pulmonary arterial hypertension with a dual ETA/ETB receptors antagonist in the apolipoprotein E−/− model of PAH and atherosclerosis

Idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients who also have an increased risk of comorbid atherosclerosis. Apolipoprotein E deficient (ApoE-/-) mice develop atherosclerosis with severe PAH when fed a high-fat diet (HFD), and have increased levels of endothelin (ET)-1. ET-1 receptor antagonists (ERAs) are used for the treatment of PAH but less is known about whether ERAs are beneficial in atherosclerosis. We therefore examined whether treatment of HFD-ApoE-/- mice with macitentan, a dual ETA/ETB receptor antagonist, would have any effect on both atherosclerosis and PAH. ApoE-/- mice were fed chow or HFD for 8 weeks. After 4 weeks of HFD, mice were randomised to a 4-week treatment of macitentan by food (30mg/kg/day dual ETA/ETB antagonist), or placebo groups. Echocardiography and closed-chest right heart catheterisation were used to determine PAH phenotype and serum samples were collected for cytokine analysis. Thoracic aortas were harvested to assess vascular reactivity using wire myography, and histological analyses were performed on the brachiocephalic artery and aortic root to assess atherosclerotic burden. Macitentan treatment of HFD-fed ApoE-/- mice was associated with a beneficial effect on the PAH phenotype and led to an increase in endothelial-dependent relaxation in thoracic aortae. Macitentan treatment was also associated with a significant reduction in interleukin 6 (IL-6) concentration but there was no significant effect on atherosclerotic burden. Dual blockade of ETA/ETB receptors improves endothelial function and improves experimental PAH but had no significant effect on atherosclerosis

Islet Endothelial Activation and Oxidative Stress Gene Expression Is Reduced by IL-1Ra Treatment in the Type 2 Diabetic GK Rat

Inflammation followed by fibrosis is a component of islet dysfunction in both rodent and human type 2 diabetes. Because islet inflammation may originate from endothelial cells, we assessed the expression of selected genes involved in endothelial cell activation in islets from a spontaneous model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We also examined islet endotheliuml/oxidative stress (OS)/inflammation-related gene expression, islet vascularization and fibrosis after treatment with the interleukin-1 (IL-1) receptor antagonist (IL-1Ra)

ROLE DE L'ENDOTHELINE-1 DANS LA REGULATION DE LA FONCTION VASCULAIRE A COURT ET LONG TERME

EN REPONSE A DES VARIATIONS METABOLIQUES ET/OU HEMODYNAMIQUES TELLES QUE LE FLUX ET LA PRESSION, LES ARTERES PEUVENT REAGIR A COURT TERME EN MODIFIANT LEUR DIAMETRE VIA LA PRODUCTION ENDOTHELIALE D'AGENTS VASOACTIFS, SOIT, A PLUS LONG TERME, EN MODIFIANT LEUR STRUCTURE (REMODELAGE) OU EN PRODUISANT DE NOUVEAUX VAISSEAUX (ANGIOGENESE). CE TRAVAIL A CONSISTE A ETUDIER LE ROLE D'UNE HORMONE VASOACTIVE, L'ENDOTHELINE-1 (ET-1), SUR LA PHYSIOPATHOLOGIE DES ARTERES DE RESISTANCES, CONNUES POUR LEUR ROLE CLE DANS LE MAINTIEN DE LA PRESSION ARTERIELLE. LA PREMIERE PARTIE DE CE TRAVAIL A ETE D'ETUDIER L'IMPACT D'UN BLOCAGE OU D'UNE ACTIVATION CHRONIQUE DES RECEPTEURS DE L'ET-1 SUR LA FONCTION ENDOTHELIALE D'ARTERES DE RESISTANCE D'ANIMAUX NORMO-ET HYPERTENDUS. LES RESULTATS OBTENUS MONTRENT QUE LE SYSTEME ENDOTHELINE MODIFIE LA FONCTION ENDOTHELIALE DE CES ANIMAUX VIA LA MODULATION DE LA PRODUCTION D'OXYDE NITRIQUE ET DE PROSTAGLANDINES VASOCONSTRICTRICES/VASODILATATRICES PAR LES RECEPTEURS ET-A/ET-B. NOUS AVONS EGALEMENT MONTRE QUE LE POLYMORPHISME LYS198ASN DU GENE DE LA PREPRO-ENDOTHELINE, ASSOCIE DANS UNE PRECEDENTE ETUDE A UNE HYPERTENSION ARTERIELLE, ETAIT EGALEMENT ASSOCIE A UNE MODIFICATION DE LA REACTIVITE VASCULAIRE IN VITRO ET QUE LES PATIENTS POSSEDANT LA MUTATION PRESENTAIENT UNE AUGMENTATION DE LA POTENTIALISATION PAR L'ET-1 DE LA REPONSE A LA PHENYLEPHRINE AINSI QU'UNE AUGMENTATION DE LA SENSIBILITE DE L'APPAREIL CONTRACTILE AU CALCIUM. DANS LA DERNIERE PARTIE, LE BUT DE NOTRE DEMARCHE A ETE D'ETUDIER LE ROLE ANGIOGENIQUE DE L'ET-1 IN VIVO DANS UN MODELE D'ANGIOGENESE INDUITE PAR ISCHEMIE DANS LA PATTE DE RAT, ET D'ESSAYER DE PROPOSER UN MECANISME CELLULAIRE A CE PHENOMENE. NOS RESULTATS MONTRENT QUE L'ET-1 SEMBLE ETRE UN REGULATEUR NEGATIF DE L'ANGIOGENESE, CONTRAIREMENT A CE QUE LAISSAIENT PREVOIR LES ETUDES MENEES IN VITRO ET QUE LE BLOCAGE CHRONIQUE DES RECEPTEURS A L'ET-1 AUGMENTE L'ANGIOGENESE VIA L'ACTIVATION DU VEGF ET DE L'OXYDE NITRIQUE.PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Clozel M. At the heart of tissue: endothelin system and endorgan damage. Clin Sci (Lond

A B S T R A C T ET (endothelin)-1 was first described as a potent vasoconstrictor. Since then, many other deleterious properties mediated via its two receptors, ET A and ET B , have been described, such as inflammation, fibrosis and hyperplasia. These effects, combined with a wide tissue distribution of the ET system, its up-regulation in pathological situations and a local autocrine/paracrine activity due to a high tissue receptor binding, make the tissue ET system a key local player in end-organ damage. Furthermore, ET-1 interacts in tissues with other systems such as the RAAS (renin-angiotensin-aldosterone system) to exert its effects. In numerous genetically modified animal models, non-specific or organ-targeted ET-1 overexpression causes intense organ damage, especially hypertrophy and fibrosis, in the absence of haemodynamic changes, confirming a local activity of the ET system. ET receptor antagonists have been shown to prevent and sometimes reverse these tissue alterations in an organ-specific manner, leading to long-term benefits and an improvement in survival in different animal models. Potential for such benefits going beyond a pure haemodynamic effect have also been suggested by clinical trial results in which ET receptor antagonism decreased the occurrence of new digital ulcers in patients with systemic sclerosis and delayed the time to clinical worsening in patients with PAH (pulmonary arterial hypertension). The tissue ET system allows therapeutic interventions to provide organ selectivity and beneficial effects in diseases associated with tissue inflammation, hypertrophy or fibrosis

IMPACT DU POLYMORPHISME LYS 198 DU GENE DE LA PREPRO-ENDOTHELINE-1 SUR LA REACTIVITE VASCULAIRE (DES PHARMACIE SPECIALISEE)

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF