Xiaoyong Liu1, Rui Yang2, Wenwei Bai3, Xiang Xu4, Feng Bi5, Min Zhu6, Xingkui Dou7, Hu Li8. 1. Department of Cardiovascular, the Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China. Electronic address: liuxiaoyong_416@sina.com. 2. Forensic Medicine Institution, Kunming Medical University, Kunming, 650500, China. Electronic address: ruiyang19820823@sina.com. 3. Department of Cardiovascular, the Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China. Electronic address: baiwenwei1122@sina.com. 4. Department of Cardiovascular, the Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China. Electronic address: robben1990@sina.com. 5. Department of Cardiovascular, the Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China. Electronic address: bifeng756240910@sina.com. 6. Department of Cardiovascular, the Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China. Electronic address: zhumin2019@sina.com. 7. Department of Cardiovascular, the Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China. Electronic address: douxingkui2019@sina.com. 8. Department of Cardiovascular, the Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China. Electronic address: lihu0416@sina.cn.
Abstract
AIM: The present study explored the role and possible interrelationship between orexin B-sirtuin 1-HIF-1α signaling pathways in diabetes-mellitus induced vascular dysfunction and enhancement in myocardial injury. MATERIAL AND METHODS: Streptozotocin (60 mg/kg) was employed to induce diabetes mellitus in male Wistar albino rats, which were kept for eight weeks. The vascular function was noted by assessing acetylcholine-induced relaxation in norepinephrine precontracted mesenteric arteries. The hearts were subjected to ischemia-reperfusion injury on the Langendorff apparatus. Myocardial injury was assessed by noting the release of CK-MB, cardiac troponin and measuring myocardial infarction. The levels of orexin B, sirtuin 1 and HIF-1α were measured. YNT-185 (orexin B type 2 receptor agonist), STR2104 (sirtuin 1 agonist) and EX527 (sirtuin 1 antagonist) were employed as pharmacological tools. RESULTS: Diabetes led to significant development of vascular dysfunction and enhanced ischemia-reperfusion injury in isolated hearts. There was a significant decrease in the levels of orexin B, sirtuin 1 and HIF-1α in diabetic animals. Treatment with YNT-185 and/or STR2104 significantly attenuated the diabetes-induced increase in myocardial injury and vascular dysfunction. Co-administration of EX527 abolished the effects of YNT-185 suggesting orexin B-mediated effects may be through activation of sirtuin 1. Moreover, YNT-185-induced increase in the expression of sirtuin 1 and HIF-1α was also abolished in the presence of EX527. CONCLUSION: Diabetes-induced significant decline in orexin B levels in the plasma along with a decrease in the expression of sirtuin 1 and HIF-1α in the heart following ischemia-reperfusion injury may possibly contribute in exacerbating the myocardial injury and vascular dysfunction.
AIM: The present study explored the role and possible interrelationship between orexin B-sirtuin 1-HIF-1α signaling pathways in diabetes-mellitus induced vascular dysfunction and enhancement in myocardial injury. MATERIAL AND METHODS:Streptozotocin (60 mg/kg) was employed to induce diabetes mellitus in male Wistar albino rats, which were kept for eight weeks. The vascular function was noted by assessing acetylcholine-induced relaxation in norepinephrine precontracted mesenteric arteries. The hearts were subjected to ischemia-reperfusion injury on the Langendorff apparatus. Myocardial injury was assessed by noting the release of CK-MB, cardiac troponin and measuring myocardial infarction. The levels of orexin B, sirtuin 1 and HIF-1α were measured. YNT-185 (orexin B type 2 receptor agonist), STR2104 (sirtuin 1 agonist) and EX527 (sirtuin 1 antagonist) were employed as pharmacological tools. RESULTS:Diabetes led to significant development of vascular dysfunction and enhanced ischemia-reperfusion injury in isolated hearts. There was a significant decrease in the levels of orexin B, sirtuin 1 and HIF-1α in diabetic animals. Treatment with YNT-185 and/or STR2104 significantly attenuated the diabetes-induced increase in myocardial injury and vascular dysfunction. Co-administration of EX527 abolished the effects of YNT-185 suggesting orexin B-mediated effects may be through activation of sirtuin 1. Moreover, YNT-185-induced increase in the expression of sirtuin 1 and HIF-1α was also abolished in the presence of EX527. CONCLUSION:Diabetes-induced significant decline in orexin B levels in the plasma along with a decrease in the expression of sirtuin 1 and HIF-1α in the heart following ischemia-reperfusion injury may possibly contribute in exacerbating the myocardial injury and vascular dysfunction.