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(Circulation. 2000;101:2083.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Analysis of the Human G Protein–Coupled Receptor Kinase 2 (GRK2) Gene Promoter

Regulation by Signal Transduction Systems in Aortic Smooth Muscle Cells

Ricardo Ramos-Ruiz, PhD; Petronila Penela, PhD; Raymond B. Penn, PhD; Federico Mayor, Jr, PhD

From the Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain (R.R.-R., P.P., F.M.), and the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pa (R.B.P.).

Correspondence to Dr Federico Mayor, Jr, Centro de Biología Molecular Severo Ochoa, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049 Madrid, Spain. E-mail fmayor{at}cbm.uam.es

Background—Desensitization of G protein–coupled receptors (GPCR) is emerging as an important feature of several cardiovascular diseases. G protein–coupled receptor kinase 2 (GRK2) plays a key role in the regulation of a variety of these receptors, and its cardiac expression levels are altered in pathological situations such as chronic heart failure. However, very little is known about the signals and mechanisms that modulate GRK2 expression in cardiovascular cells.

Methods and Results—We have studied the transcriptional activity of the 1.6-kb-long proximal genomic region of the human GRK2 gene. In an aortic smooth muscle cell line, agents that lead to physiological vasoconstriction and hypertrophy, such as phorbol esters, increased GRK2 promoter activity. Activation of signaling pathways by cotransfected G_q subunits or ₁-adrenergic receptors also markedly enhanced the expression of the GRK2 promoter constructs. Conversely, proinflammatory cytokines, such as interleukin-1ß, tumor necrosis factor-, or interferon-, led to the opposite effect, decreasing the activity of the GRK2 promoter.

Conclusions—Our results suggest that the expression of GRK2 in vascular cells is tightly controlled at the transcriptional level by the interplay between several extracellular messengers, which may trigger alterations of normal GRK2 levels in some physiopathological circumstances, thus promoting changes in the efficacy of the GPCR signal transduction.

Key Words: kinase • signal transduction • muscle, smooth • heart failure

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