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G protein coupled receptor kinase-2 upregulation causes ¿-opioid receptor desensitization in diabetic heart.

Authors: Chen, Xiyao  Zhao, Shihao  Xia, Yunlong  Xiong, Zhenyu  Li, Yueyang  Tao, Ling  Zhang, Fuyang  Wang, Xiaoming 
Citation: Chen X, etal., Biochem Biophys Res Commun. 2017 Jan 22;482(4):658-664. doi: 10.1016/j.bbrc.2016.11.090. Epub 2016 Nov 16.
Pubmed: (View Article at PubMed) PMID:27865836
DOI: Full-text: DOI:10.1016/j.bbrc.2016.11.090

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.


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CRRD Object Information
CRRD ID: 13513990
Created: 2018-03-20
Species: All species
Last Modified: 2018-03-20
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.