Irisin attenuates angiotensin II-induced cardiac fibrosis via Nrf2 mediated inhibition of ROS/ TGFβ1/Smad2/3 signaling axis

Chem Biol Interact. 2019 Apr 1:302:11-21. doi: 10.1016/j.cbi.2019.01.031. Epub 2019 Jan 29.

Abstract

Angiotensin II-related cardiac fibrosis is one of the key pathological changes of the hypertrophied left ventricle in various heart disease. Irisin was recently reported to confer cardio-protective and anti-oxidative effects, while whether it can reverse the renin-angiotensin-aldosterone system(RAAS) activation related(angiotensin II-induced) cardiac fibrosis is unknown. In this study, we found that angiotensin II-induced cardiac dysfunction and fibrotic responses were dampened by irisin treatment in mice. Mechanistically, angiotensin II induced robust ROS generation, which in turn triggered activation of pro-fibrotic TGFβ1-Smad2/3 signaling and subsequent collagen synthesis and fibroblast-myofibroblast transformation in cardiac fibroblasts. In contrast, Irisin treatment suppressed angiotensin II-induced ROS generation, TGFβ1 activation, collagen synthesis and fibroblast-myofibroblast transformation, the effects of which was accompanied by Nrf2 activation and also abolished by a Nrf2 targeted siRNA. Taken together, we here identified irisin as a promising anti-fibrotic therapeutic for angiotensin II-related cardiac fibrosis.

Keywords: Angiotensin II; Fibrosis; Heart; Oxidative stress.

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibronectins / pharmacology*
  • Fibrosis
  • Heart Diseases / metabolism
  • Heart Diseases / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / cytology
  • NF-E2-Related Factor 2 / antagonists & inhibitors
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / drug effects
  • Protective Agents / pharmacology*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects*
  • Smad2 Protein / metabolism
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta1 / metabolism

Substances

  • FNDC5 protein, mouse
  • Fibronectins
  • NF-E2-Related Factor 2
  • Protective Agents
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Smad2 Protein
  • Smad3 Protein
  • Transforming Growth Factor beta1
  • Angiotensin II