Nuclear effects of G-protein receptor kinase 5 on histone deacetylase 5-regulated gene transcription in heart failure

Yan Zhang, Scot J. Matkovich, Xiujun Duan, Jessica I. Gold, Walter J. Koch, Gerald W. Dorn

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Background: G-protein receptor kinases (GRKs) modulate cardiac β-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 Gaq-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 Gaq-dependent transcriptional regulation. In vitro, GRK5 stimulated HDAC5 nuclear export only in the context of Gaq 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 Gaq 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 Gaq down-regulated mRNAs. Conclusions: GRK5 is a transcriptional modifier of a subset of Gaq-downregulated genes, acting in opposition to the pathological effects of Gaq and normalizing levels of these transcripts. This transcriptional coregulator effect may act in concert with β-adrenergic receptor desensitization to protect against heart failure decompensation.

Original languageEnglish
Pages (from-to)659-668
Number of pages10
JournalCirculation: Heart Failure
Volume4
Issue number5
DOIs
StatePublished - Sep 2011

Keywords

  • Cardiomyopathy
  • G-protein receptor kinase
  • Gene expression

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