{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:08:27Z","timestamp":1789999707501,"version":"4.0.1"},"reference-count":63,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","funder":[{"name":"the National Key R&amp;D Program of China","award":["2018YFA0800501,2018YFA0800701,2018YFA0507603"],"award-info":[{"award-number":["2018YFA0800501,2018YFA0800701,2018YFA0507603"]}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["31671177,81630008,81790621,81872752,31521062"],"award-info":[{"award-number":["31671177,81630008,81790621,81872752,31521062"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Beijing Natural Science Foundation","award":["5182010"],"award-info":[{"award-number":["5182010"]}]}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2021,1,22]]},"abstract":"<jats:sec>\n            <jats:title>Rationale:<\/jats:title>\n            <jats:p>\n              The \u03b2\n              <jats:sub>2<\/jats:sub>\n              -adrenoceptor (\u03b2\n              <jats:sub>2<\/jats:sub>\n              -AR), a prototypical GPCR (G protein-coupled receptor), couples to both G\n              <jats:sub>s<\/jats:sub>\n              and G\n              <jats:sub>i<\/jats:sub>\n              proteins. Stimulation of the \u03b2\n              <jats:sub>2<\/jats:sub>\n              -AR is beneficial to humans and animals with heart failure presumably because it activates the downstream G\n              <jats:sub>i<\/jats:sub>\n              -PI3K-Akt cell survival pathway. Cardiac \u03b2\n              <jats:sub>2<\/jats:sub>\n              -AR signaling can be regulated by crosstalk or heterodimerization with other GPCRs, but the physiological and pathophysiological significance of this type of regulation has not been sufficiently demonstrated.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>\n              Here, we aim to investigate the potential cardioprotective effect of \u03b2\n              <jats:sub>2<\/jats:sub>\n              -adrenergic stimulation with a subtype-selective agonist, (R,R\u2019)-4-methoxy-1-naphthylfenoterol (MNF), and to decipher the underlying mechanism with a particular emphasis on the role of heterodimerization of \u03b2\n              <jats:sub>2<\/jats:sub>\n              -ARs with another GPCR, 5-hydroxytryptamine receptors 2B (5-HT\n              <jats:sub>2B<\/jats:sub>\n              Rs).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              Using pharmacological, genetic and biophysical protein-protein interaction approaches, we studied the cardioprotective effect of the \u03b2\n              <jats:sub>2<\/jats:sub>\n              -agonist, MNF, and explored the underlying mechanism in both in vivo in mice and cultured rodent cardiomyocytes insulted with doxorubicin, hydrogen peroxide (H\n              <jats:sub>2<\/jats:sub>\n              O\n              <jats:sub>2<\/jats:sub>\n              ) or ischemia\/reperfusion. In doxorubicin (Dox)-treated mice, MNF reduced mortality and body weight loss, while improving cardiac function and cardiomyocyte viability. MNF also alleviated myocardial ischemia\/reperfusion injury. In cultured rodent cardiomyocytes, MNF inhibited DNA damage and cell death caused by Dox, H\n              <jats:sub>2<\/jats:sub>\n              O\n              <jats:sub>2<\/jats:sub>\n              or hypoxia\/reoxygenation. Mechanistically, we found that MNF or another \u03b2\n              <jats:sub>2<\/jats:sub>\n              -agonist zinterol markedly promoted heterodimerization of \u03b2\n              <jats:sub>2<\/jats:sub>\n              -ARs with 5-HT\n              <jats:sub>2B<\/jats:sub>\n              Rs. Upregulation of the heterodimerized 5-HT\n              <jats:sub>2B<\/jats:sub>\n              Rs and \u03b2\n              <jats:sub>2<\/jats:sub>\n              -ARs enhanced \u03b2\n              <jats:sub>2<\/jats:sub>\n              -AR-stimulated G\n              <jats:sub>i<\/jats:sub>\n              -Akt signaling and cardioprotection while knockdown or pharmacological inhibition of the 5-HT\n              <jats:sub>2B<\/jats:sub>\n              R attenuated \u03b2\n              <jats:sub>2<\/jats:sub>\n              -AR-stimulated G\n              <jats:sub>i<\/jats:sub>\n              signaling and cardioprotection.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              These data demonstrate that the \u03b2\n              <jats:sub>2<\/jats:sub>\n              -AR-stimulated cardioprotective G\n              <jats:sub>i<\/jats:sub>\n              signaling depends on the heterodimerization of \u03b2\n              <jats:sub>2<\/jats:sub>\n              -ARs and 5-HT\n              <jats:sub>2B<\/jats:sub>\n              Rs.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.120.317011","type":"journal-article","created":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T10:02:10Z","timestamp":1605780130000},"page":"262-277","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":37,"title":["Heterodimerization With 5-HT\n            <sub>2B<\/sub>\n            R Is Indispensable for \u03b2\n            <sub>2<\/sub>\n            AR-Mediated Cardioprotection"],"prefix":"10.1161","volume":"128","author":[{"given":"Ying","family":"Song","sequence":"first","affiliation":[{"name":"State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China (Y.S., D.S., X.H., Y.Z., A.Y.-H.W., 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