Heterodimerization With 5-HT _2B R Is Indispensable for ? ₂ AR-Mediated Cardioprotection

Rationale: The ? 2 -adrenoceptor (? -AR), a prototypical GPCR (G protein-coupled receptor), couples to both G s and i proteins. Stimulation of the -AR is beneficial humans animals with heart failure presumably because it activates downstream -PI3K-Akt cell survival pathway. Cardiac signaling can be regulated by crosstalk or heterodimerization other GPCRs, but physiological pathophysiological significance this type regulation has not been sufficiently demonstrated. Objective: Here, we aim investigate potential cardioprotective effect -adrenergic stimulation subtype-selective agonist, (R,R’)-4-methoxy-1-naphthylfenoterol (MNF), decipher underlying mechanism particular emphasis on role -ARs another GPCR, 5-hydroxytryptamine receptors 2B (5-HT Rs). Methods Results: Using pharmacological, genetic biophysical protein-protein interaction approaches, studied -agonist, MNF, explored in vivo mice cultured rodent cardiomyocytes insulted doxorubicin, hydrogen peroxide (H O ) ischemia/reperfusion. In doxorubicin (Dox)-treated mice, MNF reduced mortality body weight loss, while improving cardiac function cardiomyocyte viability. also alleviated myocardial ischemia/reperfusion injury. cardiomyocytes, inhibited DNA damage death caused Dox, H hypoxia/reoxygenation. Mechanistically, found that -agonist zinterol markedly promoted 5-HT Rs. Upregulation heterodimerized Rs enhanced -AR-stimulated -Akt cardioprotection knockdown pharmacological inhibition R attenuated cardioprotection. Conclusions: These data demonstrate depends