Nur77 protects against adverse cardiac remodelling by limiting neuropeptide Y signalling in the sympathoadrenal-cardiac axis

Cardiovasc Res. 2018 Oct 1;114(12):1617-1628. doi: 10.1093/cvr/cvy125.

Abstract

Aims: Cardiac remodelling and heart failure are promoted by persistent sympathetic activity. We recently reported that nuclear receptor Nur77 may protect against sympathetic agonist-induced cardiac remodelling in mice. The sympathetic co-transmitter neuropeptide Y (NPY) is co-released with catecholamines and is a known cardiac modulator and predictor of heart failure mortality. Recently, transcriptome analyses revealed NPY as a putative target of Nur77. In this study, we assess whether Nur77 modulates adverse cardiac remodelling via NPY signalling.

Methods and results: Nur77 represses NPY expression in the PC12 adrenal chromaffin cell line. Accordingly, NPY levels are higher in adrenal gland, plasma, and heart from Nur77-KO compared to wild-type mice. Conditioned medium from Nur77-silenced chromaffin cells and serum from Nur77-KO mice induce marked hypertrophy in cultured neonatal rat cardiomyocytes, which is inhibited by the NPY type 1 receptor (NPY1R) antagonist BIBO3304. In cardiomyocytes from Nur77-KO mice, intracellular Ca2+ is increased partially via the NPY1R. This is independent from elevated circulating NPY since cardiomyocyte-specific Nur77-deficient mice (CM-KO) do not have elevated circulating NPY, but do exhibit BIBO3304-sensitive, increased cardiomyocyte intracellular Ca2+. In vivo, this translates to NPY1R antagonism attenuating cardiac calcineurin activity and isoproterenol-induced cardiomyocyte hypertrophy and fibrosis in full-body Nur77-KO mice, but not in CM-KO mice.

Conclusions: The cardioprotective action of Nur77 can be ascribed to both inhibition of circulating NPY levels and to cardiomyocyte-specific modulation of NPY-NPY1R signalling. These results reveal the underlying mechanism of Nur77 as a promising modifier gene in heart failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Glands / metabolism*
  • Animals
  • Calcineurin / metabolism
  • Calcium Signaling
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Cardiomegaly / prevention & control*
  • Female
  • Fibrosis
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Neuropeptide Y / genetics
  • Neuropeptide Y / metabolism*
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / deficiency
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • PC12 Cells
  • Rats
  • Rats, Wistar
  • Receptors, Neuropeptide Y / metabolism
  • Sympathetic Nervous System / metabolism*
  • Sympathetic Nervous System / physiopathology
  • Ventricular Remodeling*

Substances

  • NR4A1 protein, human
  • Neuropeptide Y
  • Nr4a1 protein, mouse
  • Nr4a1 protein, rat
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Neuropeptide Y
  • neuropeptide Y-Y1 receptor
  • Calcineurin