Fleur Bossi1, Stella Bernardi2, Daniele De Nardo2, Alessandra Bramante2, Riccardo Candido3, Renzo Carretta2, Fabio Fischetti2, Bruno Fabris2. 1. Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Strada di Fiume 447, 34100 Trieste, Italy. Electronic address: fbossi@units.it. 2. Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital, Strada di Fiume 447, 34100 Trieste, Italy. 3. Centro Diabetologico ASS 1 Triestina, Via Puccini, 34100 Trieste, Italy.
Abstract
OBJECTIVE: Recent studies have demonstrated that Ang1-7 has anti-inflammatory effects. Since the formation of Ang1-7 is significantly altered in the setting of diabetes, here we aimed to evaluate whether Ang1-7 infusion could ameliorate diabetes-induced leukocyte recruitment. METHODS: Wild-type male Wistar rats were randomly allocated to the following groups: control + saline, control + Ang1-7, diabetes + saline, diabetes + Ang1-7. Diabetes was induced by streptozotocin. Saline and Ang1-7 (576 μg/kg/day) were injected intraperitoneally daily. After 4 weeks leukocyte trafficking was studied in vivo by intravital microscopy in the mesenteric bed, where the expression of pro-oxidative, proinflammatory, and profibrotic molecules was also assessed. In parallel in vitro studies, HUVEC were grown in 5 mM, 22 mM, 30 mM, 40 mM, 50 mM, and 75 mM glucose media for 48 h, 72 h and 6 days and were treated either with placebo, or with Ang1-7, or with Ang1-7 and its inhibitor A779 in order to evaluate the expression of ICAM-1 and VCAM-1. We further studied leukocytes recruitment in vitro by evaluating PMN-HUVEC adhesion. RESULTS: Ang1-7 prevented in vivo diabetes-induced leukocyte adhesion and extravasation, and it significantly reduced vascular hypertrophy and the other molecular changes due to diabetes. Ang 1-7 prevented also in vitro the hyperglycemia-induced increase of ICAM-1 and VCAM-1 as well as the hyperglycemia-induced PMN adhesion. A779 inhibited Ang 1-7 effects. CONCLUSIONS: Ang1-7 significantly reduced diabetes-induced leukocyte recruitment both in vivo and in vitro. These findings emphasize the potential utility of ACE2/Ang1-7/Mas repletion as a strategy to reduce diabetes-induced atherosclerosis.
OBJECTIVE: Recent studies have demonstrated that Ang1-7 has anti-inflammatory effects. Since the formation of Ang1-7 is significantly altered in the setting of diabetes, here we aimed to evaluate whether Ang1-7 infusion could ameliorate diabetes-induced leukocyte recruitment. METHODS: Wild-type male Wistar rats were randomly allocated to the following groups: control + saline, control + Ang1-7, diabetes + saline, diabetes + Ang1-7. Diabetes was induced by streptozotocin. Saline and Ang1-7 (576 μg/kg/day) were injected intraperitoneally daily. After 4 weeks leukocyte trafficking was studied in vivo by intravital microscopy in the mesenteric bed, where the expression of pro-oxidative, proinflammatory, and profibrotic molecules was also assessed. In parallel in vitro studies, HUVEC were grown in 5 mM, 22 mM, 30 mM, 40 mM, 50 mM, and 75 mM glucose media for 48 h, 72 h and 6 days and were treated either with placebo, or with Ang1-7, or with Ang1-7 and its inhibitor A779 in order to evaluate the expression of ICAM-1 and VCAM-1. We further studied leukocytes recruitment in vitro by evaluating PMN-HUVEC adhesion. RESULTS:Ang1-7 prevented in vivo diabetes-induced leukocyte adhesion and extravasation, and it significantly reduced vascular hypertrophy and the other molecular changes due to diabetes. Ang 1-7 prevented also in vitro the hyperglycemia-induced increase of ICAM-1 and VCAM-1 as well as the hyperglycemia-induced PMN adhesion. A779 inhibited Ang 1-7 effects. CONCLUSIONS:Ang1-7 significantly reduced diabetes-induced leukocyte recruitment both in vivo and in vitro. These findings emphasize the potential utility of ACE2/Ang1-7/Mas repletion as a strategy to reduce diabetes-induced atherosclerosis.
Authors: Ahmed Z El-Hashim; Maitham A Khajah; Rhema S Babyson; Waleed M Renno; Charles I Ezeamuzie; Ibrahim F Benter; Saghir Akhtar Journal: PLoS One Date: 2019-11-01 Impact factor: 3.240