β-肾上腺素能受体介导的心肌收缩力通过1A型血管加压素受体依赖性信号传导受到抑制。
β-adrenergic receptor-mediated cardiac contractility is inhibited via vasopressin type 1A-receptor-dependent signaling.
作者信息
Tilley Douglas G, Zhu Weizhong, Myers Valerie D, Barr Larry A, Gao Erhe, Li Xue, Song Jianliang, Carter Rhonda L, Makarewich Catherine A, Yu Daohai, Troupes Constantine D, Grisanti Laurel A, Coleman Ryan C, Koch Walter J, Houser Steven R, Cheung Joseph Y, Feldman Arthur M
机构信息
From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
出版信息
Circulation. 2014 Nov 11;130(20):1800-11. doi: 10.1161/CIRCULATIONAHA.114.010434. Epub 2014 Sep 9.
BACKGROUND
Enhanced arginine vasopressin levels are associated with increased mortality during end-stage human heart failure, and cardiac arginine vasopressin type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted V1AR overexpression develop cardiomyopathy and decreased β-adrenergic receptor (βAR) responsiveness. This led us to hypothesize that V1AR signaling regulates βAR responsiveness and in doing so contributes to development of heart failure.
METHODS AND RESULTS
Transaortic constriction resulted in decreased cardiac function and βAR density and increased cardiac V1AR expression, effects reversed by a V1AR-selective antagonist. Molecularly, V1AR stimulation led to decreased βAR ligand affinity, as well as βAR-induced Ca(2+) mobilization and cAMP generation in isolated adult cardiomyocytes, effects recapitulated via ex vivo Langendorff analysis. V1AR-mediated regulation of βAR responsiveness was demonstrated to occur in a previously unrecognized Gq protein-independent/G protein receptor kinase-dependent manner.
CONCLUSIONS
This newly discovered relationship between cardiac V1AR and βAR may be informative for the treatment of patients with acute decompensated heart failure and elevated arginine vasopressin.
背景
在终末期人类心力衰竭期间，精氨酸加压素水平升高与死亡率增加相关，且心脏1A型精氨酸加压素受体（V1AR）表达增加。此外，心脏特异性V1AR过表达的小鼠会发生心肌病，且β肾上腺素能受体（βAR）反应性降低。这使我们推测V1AR信号传导调节βAR反应性，并由此促进心力衰竭的发展。
方法与结果
经主动脉缩窄导致心脏功能和βAR密度降低，心脏V1AR表达增加，V1AR选择性拮抗剂可逆转这些效应。在分子水平上，V1AR刺激导致βAR配体亲和力降低，以及在分离的成年心肌细胞中βAR诱导的Ca(2+)动员和cAMP生成，通过离体Langendorff分析再现了这些效应。V1AR介导的βAR反应性调节被证明是以一种先前未被认识的不依赖Gq蛋白/依赖G蛋白受体激酶的方式发生的。
结论
心脏V1AR与βAR之间这种新发现的关系可能为治疗急性失代偿性心力衰竭和精氨酸加压素升高的患者提供信息。
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