title: 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.affiliation: Nantong University School of Pharmacy, Nantong, China.
authors.forename: Weizhong
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, Maryland, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Tsang
authors.affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, Maryland, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Browe
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing, China.|School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Anthony Yh
authors.initials: AY
authors.lastname: Woo
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Chanjuan
authors.initials: C
authors.lastname: Xu
authors.affiliation: School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Lv
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing, China.|Peking-Tsinghua Center for Life Sciences and.|Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao