Analysis of the human G protein-coupled receptor kinase 2 (GRK2) gene promoter - Regulation by signal transduction systems in aortic smooth muscle cells

Article

关键词: NITRIC-OXIDE;    ACTIVATION;    MICE;    DESENSITIZATION;    OVEREXPRESSION;    EXPRESSION;    MECHANISM;    PATHWAY;    HEART;   

DOI  :  10.1161/01.CIR.101.17.2083

来源: SCIE

【 摘 要 】

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 eaters, increased GRK2 promoter activity. Activation of signaling pathways by cotransfected G(alpha q) subunits or alpha(1)-adrenergic receptors also markedly enhanced the expression of the GRK2 promoter constructs. Conversely, proinflammatory cytokines, such as interleukin-1 beta, tumor necrosis factor-alpha, or interferon-gamma, 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.

【 授权许可】

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