Sorriento Daniela, Santulli Gaetano, Franco Antonietta, Cipolletta Ersilia, Napolitano Luigi, Gambardella Jessica, Gomez-Monterrey Isabel, Campiglia Pietro, Trimarco Bruno, Iaccarino Guido, Ciccarelli Michele
Institute of Biostructure and Bioimaging (IBB) of the Italian National Research Council (CNR), Naples, Italy.
College of Physicians & Surgeons, New York Presbyterian Hospital - Manhattan, Columbia University Medical Center, New York, NY, USA.
J Cardiovasc Transl Res. 2015 Nov;8(8):493-502. doi: 10.1007/s12265-015-9646-0. Epub 2015 Jul 30.
G protein coupled receptor kinase type 2 (GRK2) plays an important role in the development and maintenance of cardiac hypertrophy and heart failure even if its exact role is still unknown. In this study, we assessed the effect of GRK2 on the regulation of cardiac hypertrophy. In H9C2 cells, GRK2 overexpression increased atrial natriuretic factor (ANF) activity and enhanced phenylephrine-induced ANF response, and this is associated with an increase of NFκB transcriptional activity. The kinase dead mutant and a synthetic inhibitor of GRK2 activity exerted the opposite effect, suggesting that GRK2 regulates hypertrophy through upregulation of NFκB activity in a phosphorylation-dependent manner. In two different in vivo models of left ventricle hypertrophy (LVH), the selective inhibition of GRK2 activity prevented hypertrophy and reduced NFκB transcription activity. Our results suggest a previously undisclosed role for GRK2 in the regulation of hypertrophic responses and propose GRK2 as potential therapeutic target for limiting LVH.
G蛋白偶联受体激酶2（GRK2）在心肌肥大和心力衰竭的发生发展及维持过程中发挥着重要作用，尽管其确切作用仍不清楚。在本研究中，我们评估了GRK2对心肌肥大调控的影响。在H9C2细胞中，GRK2过表达增加了心钠素（ANF）活性，并增强了去甲肾上腺素诱导的ANF反应，这与NFκB转录活性的增加有关。激酶失活突变体和GRK2活性的合成抑制剂产生了相反的效果，表明GRK2通过以磷酸化依赖方式上调NFκB活性来调节肥大。在两种不同的左心室肥大（LVH）体内模型中，GRK2活性的选择性抑制可预防肥大并降低NFκB转录活性。我们的结果表明GRK2在肥大反应调控中具有先前未被揭示的作用，并提出GRK2作为限制LVH的潜在治疗靶点。
