Interaction of β1-adrenoceptor with RAGE mediates cardiomyopathy via CaMKII signaling
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
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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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 4

RAGE stimulation with HMGB1 activates CaMKII in a β1AR-dependent manner.

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RAGE stimulation with HMGB1 activates CaMKII in a β1AR-dependent manner....
(A) Time course of HMGB1-induced increase in CaMKII activity, as manifested by phosphorylation of its key target, PLN, at Thr17 (P-Thr17 PLN). Top and bottom show the representative and averaged data of Western blots of P-Thr17 PLN and total PLN. Cultured adult rat cardiomyocytes were incubated with HMGB1 (200 ng/ml) for different periods of time. Data were expressed as mean ± SEM from 3 experiments; *P < 0.05; **P < 0.01; 1-way ANOVA. (B) HMGB1-induced phosphorylation of the CaMKII target PLN was abolished by sRAGE and β1AR blockade with CGP, as well. Cells were pretreated with sRAGE (14 ng/ml) or CGP (0.3 μM) for 1 hour and then incubated with HMGB1 (200 ng/ml) for another 24 hours. Top and bottom show the representative and averaged data of Western blots of P-Thr17 PLN and total PLN, respectively. Data were expressed as mean ± SEM from 3 experiments. **P < 0.01; 1-way ANOVA. RAGE, receptor for advanced glycation end-products; HMGB1, high-mobility group box 1 protein; CaMKII, Ca2+/calmodulin-dependent kinase II; sRAGE, soluble RAGE; PLN, phospholamban; CGP, CGP 20712A; Thr17, threonine 17; β1AR, β1-adrenergic receptor.