Moxonidine modulates cytokine signalling and effects on cardiac cell viability

Eur J Pharmacol. 2014 Oct 5;740:168-82. doi: 10.1016/j.ejphar.2014.06.047. Epub 2014 Jul 15.

Abstract

Regression of left ventricular hypertrophy and improved cardiac function in SHR by the centrally acting imidazoline I1-receptor agonist, moxonidine, are associated with differential actions on circulating and cardiac cytokines. Herein, we investigated cell-type specific I1-receptor (also known as nischarin) signalling and the mechanisms through which moxonidine may interfere with cytokines to affect cardiac cell viability. Studies were performed on neonatal rat cardiomyocytes and fibroblasts incubated with interleukin (IL)-1β (5 ng/ml), tumor necrosis factor (TNF)-α (10 ng/ml), and moxonidine (10(-7) and 10(-5) M), separately and in combination, for 15 min, and 24 and 48 h for the measurement of MAPKs (ERK1/2, JNK, and p38) and Akt activation and inducible NOS (iNOS) expression, by Western blotting, and cardiac cell viability/proliferation and apoptosis by flow cytometry, MTT assay, and Live/Dead assay. Participation of imidazoline I1-receptors and the signalling proteins in the detected effects was identified using imidazoline I1-receptor antagonist and signalling protein inhibitors. The results show that IL-1β, and to a lower extent, TNF-α, causes cell death and that moxonidine protects against starvation- as well as IL-1β -induced mortality, mainly by maintaining membrane integrity, and in part, by improving mitochondrial activity. The protection involves activation of Akt, ERK1/2, p38, JNK, and iNOS. In contrast, moxonidine stimulates basal and IL-1β-induced fibroblast mortality by mechanisms that include inhibition of JNK and iNOS. Thus, apart from their actions on the central nervous system, imidazoline I1-receptors are directly involved in cardiac cell growth and death, and may play an important role in cardiovascular diseases associated with inflammation.

Keywords: Apoptosis; Cardiomyocytes; Cytokines; Fibroblasts; Imidazoline I(1)- receptors; Moxonidine; Moxonidine (PubChem CID: 4810).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Antihypertensive Agents / pharmacology*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Imidazoles / pharmacology*
  • Imidazoline Receptors / metabolism
  • Interleukin-1beta / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / metabolism
  • Rats, Sprague-Dawley
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antihypertensive Agents
  • Imidazoles
  • Imidazoline Receptors
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • Nisch protein, rat
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • imidazoline I1 receptors
  • moxonidine
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase Kinases