期刊
CIRCULATION-HEART FAILURE
卷 4, 期 5, 页码 659-U193出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCHEARTFAILURE.111.962563
关键词
G-protein receptor kinase; gene expression; cardiomyopathy
资金
- National Institutes of Health from National Heart, Lung, and Blood Institute [HL087871, HL059888]
Background-G-protein receptor kinases (GRKs) modulate cardiac beta-adrenergic signaling. GRK5 is upregulated in heart failure, and a gain-of-function polymorphism substituting leucine for wild-type glutamine at amino acid 41 (GRK5-Leu41) is associated with improved outcomes in heart failure and hypertension. GRK5 is distinguished by partial nuclear localization and class II histone deacetylases (HDAC) kinase activity that is postulated to regulate G alpha q-stimulated cardiac gene expression. Methods and Results-We used in vitro tissue culture and in vivo mouse compound genetic models to examine the effects of GRK5 on HDAC phosphorylation, nucleo-cytoplasmic HDAC transport, and G alpha q-dependent transcriptional regulation. In vitro, GRK5 stimulated HDAC5 nuclear export only in the context of G alpha q signaling stimulated by angiotensin II. GRK5-Gln41 and Leu41 were similar inducers of HDAC5 nucleo-cytoplasmic shuttling. In vivo, GRK5-Gln41 and-Leu41 partitioned equally to nuclear and nonnuclear myocardial fractions. GRK5 increased cardiac HDAC5 phosphorylation and reversed the increase in nuclear HDAC5 content seen with cardiomyocyte-autonomous G alpha q overexpression. Deep RNA sequencing showed few changes in gene expression induced by GRK5 overexpression or ablation alone, but GRK5 overexpression normalized steady-state expression levels of 48% (96 of 200) of all G alpha q down-regulated mRNAs. Conclusions-GRK5 is a transcriptional modifier of a subset of G alpha q-downregulated genes, acting in opposition to the pathological effects of G alpha q and normalizing levels of these transcripts. This transcriptional coregulator effect may act in concert with beta-adrenergic receptor desensitization to protect against heart failure decompensation. (Circ Heart Fail. 2011;4:659-668.)
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