Parallel changes in neuronal at1r and grk5 expression following exercise training in heart failure

Karla K.V. Haack, Christopher W. Engler, Evlampia Papoutsi, Iraklis I. Pipinos, Kaushik P. Patel, Irving H. Zucker

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Although exercise training (ExT) is an important therapeutic strategy for improving quality of life in patients with chronic heart failure (CHF), the central mechanisms by which ExT is beneficial are not well understood. The angiotensin II type 1 receptor (AT1R) plays a pivotal role in the development of CHF and is upregulated in a number of tissues owing, in part, to transcription factor nuclear factor kappa B (NF-κB). In addition, AT1R is marked for internalization and recycling via G-protein-coupled receptor kinase (GRK) phosphorylation. Because previous studies have shown that the beneficial effects of ExT in CHF rely on a reduction in angiotensin II, we hypothesized ExT would decrease AT1R, GRK5, and NF-κB protein expression in the paraventricular nucleus and rostral ventrolateral medulla of CHF rats. Following infarction by coronary artery ligation, animals were exercised 4 weeks postsurgery on a treadmill at a final speed of 25 miles per minute for 60 minutes, 5 days per week for 6 weeks. Western blot analysis of paraventricular nucleus and rostral ventrolateral medulla micropunches revealed an upregulation of AT1R, GRK5, and NF-κB in the infarcted group that was reversed by ExT. Furthermore, the relative expression of phosphorylated AT1R and AT1R/GRK5 physical association was increased in the CHF sedentary group and reversed by ExT. Overexpression of GRK5 in cultured CATH.a neurons blunted angiotensin II-mediated upregulation of AT1R and NF-κB; conversely, silencing of GRK5 exacerbated angiotensin II-mediated AT1R and NF-κB upregulation. Taken together, increased GRK5 may regulate AT1R expression in CHF, and ExT mitigates AT1R and its pathway components.

Original languageEnglish (US)
Pages (from-to)354-361
Number of pages8
Issue number2
StatePublished - Aug 2012


  • GRK5
  • NF-βB
  • angiotensin II
  • receptor turnover

ASJC Scopus subject areas

  • Internal Medicine

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