Interaction of β1-adrenoceptor with RAGE mediates cardiomyopathy via CaMKII signaling
Weizhong Zhu, … , Yan Zhang, Rui-ping Xiao
Weizhong Zhu, … , Yan Zhang, Rui-ping Xiao
Published January 21, 2016
Citation Information: JCI Insight. 2016;1(1):e84969. https://doi.org/10.1172/jci.insight.84969.
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Research Article Cardiology Cell biology

Interaction of β1-adrenoceptor with RAGE mediates cardiomyopathy via CaMKII signaling

Abstract

Stimulation of β1-adrenergic receptor (β1AR), a GPCR, and the receptor for advanced glycation end-products (RAGE), a pattern recognition receptor (PRR), have been independently implicated in the pathogenesis of cardiomyopathy caused by various etiologies, including myocardial infarction, ischemia/reperfusion injury, and metabolic stress. Here, we show that the two distinctly different receptors, β1AR and RAGE, are mutually dependent in mediating myocardial injury and the sequelae of cardiomyopathy. Deficiency or inhibition of RAGE blocks β1AR- and RAGE-mediated myocardial cell death and maladaptive remodeling. Ablation or blockade of β1AR fully abolishes RAGE-induced detrimental effects. Mechanistically, RAGE and β1AR form a complex, which in turn activates Ca2+/calmodulin-dependent kinase II (CaMKII), resulting in loss of cardiomyocytes and myocardial remodeling. These results indicate that RAGE and β1AR not only physically crosstalk at the receptor level, but also functionally converge at the common mediator, CaMKII, highlighting a combined inhibition of RAGE and β1AR as a more effective therapy to treat diverse cardiovascular diseases, such as myocardial infarction, ischemia/reperfusion injury, and diabetic cardiovascular complications.

Authors

Weizhong Zhu, Sharon Tsang, David M. Browe, Anthony Y.H. Woo, Ying Huang, Chanjuan Xu, Jian-Feng Liu, Fengxiang Lv, Yan Zhang, Rui-ping Xiao

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Figure 5

Inhibition of RAGE signaling with sRAGE or RAGE ablation blocks ISO-induced necrotic and apoptotic cell death.

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Inhibition of RAGE signaling with sRAGE or RAGE ablation blocks ISO-indu...
(A) Deletion of RAGE diminished acute ISO treatment induced myocardial necrotic cell death, indexed by increased serum troponin I levels. Mouse serum was collected after 24-hour treatment of ISO (30 mg/kg, i.p.). Serum tropinin I was measured by ELISA (Abace-Biology). The averaged data were expressed as mean ± SEM from 4 mice for each group. **P < 0.01 as indicated; 1-way ANOVA. (B) Schematic presentation showing the experimental protocol for chronic ISO infusion in the presence or absence of cotreatment with daily sRAGE injection. (C and D) Treatment of mice with sRAGE prevents chronic ISO treatment–induced myocardial apoptotic cell death assessed by TUNEL-positive staining. Representative TUNEL staining (C) and the averaged data (D). Data were expressed as mean ± SEM from 10 mice of 3 independent experiments. **P < 0.01 versus vehicle; Student’s t test. Mice were subjected to chronic ISO treatment (60 mg/kg/d by minipump) in the presence or absence of sRAGE (8 ng/kg/d i.p.) for 7 days and then sacrificed for myocardial TUNEL staining. Scale bar: 20 μm. RAGE, receptor for advanced glycation end-products; sRAGE, soluble RAGE; ISO, isoproterenol; β1AR KO, β1-adrenergic receptor KO.