title: G protein coupled receptor kinase-2 upregulation causes κ-opioid receptor desensitization in diabetic heart.
abstract: Activation of κ-opioid receptor (KOR) ameliorates myocardial ischemia/reperfusion (I/R) injury; however, cardioprotective effects of KOR stimulation disappear in type 1 diabetic subjects with hyperglycemia. The molecular mechanisms underlying this phenomenon remain unknown. Here we found that KOR expression was obviously downregulated and KOR agonism-induced contractile-regulatory and cardioprotective effects were significantly impaired in hearts isolated from streptozotocin (STZ) injection-induced diabetic mice. These in vivo data identified cardiac KOR desensitization as a novel characteristic of the diabetic heart. In cultured cardiomyocytes, high glucose (HG) caused obvious KOR downregulation, accompanied by an upregulation of G protein coupled receptor kinase-2 (GRK2). We found that HG exposure increased the interaction between GRK2 and KOR. More importantly, HG-induced KOR downregulation was reversed by small interfering RNA (siRNA)-mediated GRK2 inhibition. GRK2 knockdown also restored KOR agonism-mediated protection against simulated I/R injury in cardiomyocytes. These in vitro data revealed an essential role of GRK2 in HG-induced KOR desensitization. Finally, cardiac-specific GRK2 knockdown by intramyocardial siRNA injection blocked KOR downregulation and restored contractile-regulatory and cardioprotective effects of KOR agonism in hearts of diabetic mice. In conclusion, these data for the first time demonstrate that GRK2 upregulation is largely responsible for cardiac KOR desensitization in diabetic individuals, which provides novel insights into the management of myocardial I/R injury in patients with diabetes.
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiyao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Shihao
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yueyang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China; Department of Cardiology, 201st Hospital of CPLA, Liaoyang 111010, China. Electronic address: plazhangfuyang@163.com.
authors.forename: Fuyang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: xmwang@fmmu.edu.cn.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003920:Diabetes Mellitus / Q000378:metabolism*; D015536:Down-Regulation; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D005947:Glucose / Q000737:chemistry; D006321:Heart / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D015427:Reperfusion Injury; D013311:Streptozocin; D015854:Up-Regulation
chemical_list: D000701:Analgesics, Opioid; D034741:RNA, Small Interfering; D017473:Receptors, Opioid, kappa; D013311:Streptozocin; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D005947:Glucose
keywords: Diabetes; G protein coupled receptor kinase-2; Ischemia/reperfusion; κ-opioid receptor