Our previous studies have shown that enhanced beta1-AR stimulation plays a central role in cardiomyocyte death via CaMKII activation. Recently, RAGE and its ligand HMGB1 have also been implicated in ischemia/reperfusion induced myocardial injury. We hypothesize that RAGE may be involved in the beta1-AR elicited cardiomyocyte death. To test the hypothesis, we selectively blocked b1AR with CGP 20712A (CGP)/atenolol, or RAGE with its decoy soluble RAGE (sRAGE), respectively, and determined whether the blockade can attenuate cardiac cell death. We found that administration of sRAGE abolished beta1-AR induced cell death;and the HMGB1-induced cell death was completely eradicated by a b1AR antagonist, CGP or atenolol, implying a functional cross-talk between these two receptors. Further studies on the downstream signaling mechanism showed that either beta1-AR or RAGE-induced cell death was abolished upon inhibition of CaMKII. Using co-immunoprecipitation and FRED assay, we also showed a physical interaction between beta1-AR and RAGE in HEK293 cells expressing both receptors. In our ongoing studies, we are focusing on the intermolecular interaction of beta1-AR with RAGE and its potential pathophysiological and therapeutic implications in gene-targeted mouse models lacking either beta1-AR or RAGE or both. These findings suggest a novel mechanism of cross-talk between beta1-AR and RAGE. The transactivation of beta1-AR/RAGE complex resulted in cardiac cell death, and CaMKII may serve as the central downstream event of this signaling pathway. Blockage of both beta1-AR and RAGE may therefore represent a novel therapeutic strategy for treating cardiovascular diseases.
