Adenylyl cyclase and G protein receptor kinase expression during development of heart failure

Am J Physiol. 1997 Aug;273(2 Pt 2):H707-17. doi: 10.1152/ajpheart.1997.273.2.H707.

Abstract

We examined alterations in left ventricular (LV) G protein receptor kinase (GRK) and adenylyl cyclase (AC) isoform expression during the development of pacing-induced congestive heart failure (CHF). AC isoform and GRK expression were assessed 4 (mild CHF) and 28 (severe CHF) days after initiation of pacing. LV beta-adrenergic receptor (beta-AR) number and G protein content were unchanged by mild CHF. LV AC isoform mRNA content was unaltered by mild CHF, but there were increases in total GRK activity (P < 0.01), total GRK5 protein content (P < 0.04), and GRK5 mRNA (P = 0.003); total GRK2 protein content and GRK2 mRNA were unchanged. Mild CHF was associated with decreased beta-AR coupling (P < 0.01) and reduced beta-AR stimulation of AC (P < 0.05). Severe CHF was associated with LV beta-AR downregulation (P = 0.0001) and uncoupling (P < 0.001) and marked generalized reduction of AC activity (mean P = 0.01). LV ACVI isoform mRNA content was reduced (P = 0.002), but ACII and ACV isoform mRNA contents were unaffected. Persistent elevations in LV total GRK activity (P < 0.01), total GRK5 protein content (P < 0.001), and GRK5 mRNA (P = 0.01) were found; in contrast, total GRK2 protein content was unchanged and GRK2 mRNA was reduced (P = 0.02). These studies indicate that increased GRK activity is an early charge in heart failure that predates alterations in AC isoform expression. Impaired hormonal stimulation of AC, associated with beta-AR uncoupling, may result from increased GRK5 expression. AC downregulation is isoform specific and accompanies severe but not mild CHF.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenylyl Cyclases / metabolism*
  • Animals
  • Body Weight
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Disease Progression
  • G-Protein-Coupled Receptor Kinase 5
  • GTP-Binding Proteins / metabolism
  • Heart Failure / metabolism*
  • Heart Failure / physiopathology*
  • Hemodynamics
  • Liver / pathology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Organ Size
  • Protein-Serine-Threonine Kinases*
  • RNA, Messenger / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Adrenergic, beta
  • Swine
  • Ventricular Function, Left
  • beta-Adrenergic Receptor Kinases

Substances

  • RNA, Messenger
  • Receptors, Adrenergic, beta
  • Receptor Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • beta-Adrenergic Receptor Kinases
  • G-Protein-Coupled Receptor Kinase 5
  • GTP-Binding Proteins
  • Adenylyl Cyclases