Traynham Christopher J, Cannavo Alessandro, Zhou Yan, Vouga Alexandre G, Woodall Benjamin P, Hullmann Jonathan, Ibetti Jessica, Gold Jessica I, Chuprun J Kurt, Gao Erhe, Koch Walter J
From the Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA (C.J.T., A.C., A.G.V., B.P.W., J.H., J.I., J.I.G., J.K.C., E.G., W.J.K.); and Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA (Y.Z.).
Circ Res. 2015 Dec 4;117(12):1001-12. doi: 10.1161/CIRCRESAHA.115.306961. Epub 2015 Oct 29.
G protein-coupled receptor kinases (GRKs) are dynamic regulators of cellular signaling. GRK5 is highly expressed within myocardium and is upregulated in heart failure. Although GRK5 is a critical regulator of cardiac G protein-coupled receptor signaling, recent data has uncovered noncanonical activity of GRK5 within nuclei that plays a key role in pathological hypertrophy. Targeted cardiac elevation of GRK5 in mice leads to exaggerated hypertrophy and early heart failure after transverse aortic constriction (TAC) because of GRK5 nuclear accumulation.
In this study, we investigated the role of GRK5 in physiological, swimming-induced hypertrophy (SIH).
Cardiac-specific GRK5 transgenic mice and nontransgenic littermate control mice were subjected to a 21-day high-intensity swim protocol (or no swim sham controls). SIH and specific molecular and genetic indices of physiological hypertrophy were assessed, including nuclear localization of GRK5, and compared with TAC. Unlike after TAC, swim-trained transgenic GRK5 and nontransgenic littermate control mice exhibited similar increases in cardiac growth. Mechanistically, SIH did not lead to GRK5 nuclear accumulation, which was confirmed in vitro as insulin-like growth factor-1, a known mediator of physiological hypertrophy, was unable to induce GRK5 nuclear translocation in myocytes. We found specific patterns of altered gene expression between TAC and SIH with GRK5 overexpression. Further, SIH in post-TAC transgenic GRK5 mice was able to preserve cardiac function.
These data suggest that although nuclear-localized GRK5 is a pathological mediator after stress, this noncanonical nuclear activity of GRK5 is not induced during physiological hypertrophy.
G蛋白偶联受体激酶（GRKs）是细胞信号传导的动态调节因子。GRK5在心肌中高度表达，且在心力衰竭时上调。尽管GRK5是心脏G蛋白偶联受体信号传导的关键调节因子，但最近的数据揭示了GRK5在细胞核内的非经典活性，其在病理性肥大中起关键作用。由于GRK5的核积累，小鼠心脏中GRK5的靶向升高会导致主动脉缩窄（TAC）后过度肥大和早期心力衰竭。
在本研究中，我们研究了GRK5在生理性游泳诱导肥大（SIH）中的作用。
将心脏特异性GRK5转基因小鼠和非转基因同窝对照小鼠进行为期21天的高强度游泳方案（或无游泳假手术对照）。评估了SIH以及生理性肥大的特定分子和遗传指标，包括GRK5的核定位，并与TAC进行比较。与TAC后不同，经游泳训练的转基因GRK5小鼠和非转基因同窝对照小鼠的心脏生长呈现相似的增加。从机制上讲，SIH不会导致GRK5核积累，这在体外得到证实，因为胰岛素样生长因子-1（一种已知的生理性肥大介质）无法诱导GRK5在心肌细胞中的核转位。我们发现了GRK5过表达时TAC和SIH之间基因表达改变的特定模式。此外，TAC后转基因GRK5小鼠中的SIH能够保留心脏功能。
这些数据表明，尽管核定位的GRK5是应激后的病理介质，但GRK5的这种非经典核活性在生理性肥大过程中不会被诱导。
