Galectin-3 mediates the pulmonary arterial hypertension-induced right ventricular remodeling through interacting with NADPH oxidase 4

J Am Soc Hypertens. 2017 May;11(5):275-289.e2. doi: 10.1016/j.jash.2017.03.008. Epub 2017 Mar 27.

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disorder that affects both pulmonary vasculature and the heart. The response of the right ventricle (RV) to the increased afterload is an important determinant of the PAH final outcome. Galectin-3 (Gal-3), a novel biomarker in left cardiac remodeling, takes part in multiple pathophysiological processes including the inflammation, fibrosis, immunity, and oxidative stress. The levels of Gal-3 are elevated in PAH patients, although the exact mechanisms underlie the PAH-induced right ventricular structural changes remain unclear. Our results showed that the serum Gal-3 and NADPH oxidase 4 (Nox4) levels were significantly elevated and correlated in 26 human PAH patients when compared with 14 age- and sex-matched healthy controls. In the monocrotaline-induced PAH rat models of right ventricular hypertrophy and fibrosis, the Gal-3 and Nox4 expressions were both significantly upregulated compared with the controls. Moreover, the Gal-3 positive areas were co-localized with the collagen III-specific staining and the Gal-3 and Nox4 were partly co-localized in the intercellular area. The exogenous Gal-3 recombinant protein stimulated the proliferation, differentiation, collagen deposition, and Nox4 expression of cardiac fibroblasts. These simulations were blocked by the Gal-3 knockdown. The profibrotic effects of transforming growth factor-β1 (TGF-β1) on the cardiac fibroblasts were partially mediated by the Gal-3. Subsequently, our results showed that Gal-3 mediated the TGF-β1-induced cardiac fibrotic process through interacting with the Nox4 and Nox4-derived oxidative stress. Therefore, Gal-3 plays an important role in the PAH-induced right ventricular remodeling through interacting with the Nox4 and Nox4-derived oxidative stress. Gal-3 may become a RV-specific diagnostic and therapeutic target for clinics.

Keywords: Galectin-3; NADPH oxidase 4; oxidative stress; right ventricular remodeling.

MeSH terms

  • Adult
  • Animals
  • Biomarkers / blood
  • Biomarkers / metabolism
  • Collagen Type III / metabolism
  • Disease Models, Animal
  • Female
  • Fibroblasts / pathology
  • Fibrosis
  • Galectin 3 / blood
  • Galectin 3 / genetics
  • Galectin 3 / metabolism*
  • Gene Knockdown Techniques
  • Heart Ventricles / pathology*
  • Humans
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / complications*
  • Male
  • Middle Aged
  • Monocrotaline / toxicity
  • Myocardium / cytology
  • Myocardium / pathology
  • Myofibroblasts / pathology
  • NADPH Oxidase 4 / blood*
  • NADPH Oxidase 4 / metabolism*
  • Oxidative Stress
  • Primary Cell Culture
  • Rats
  • Transforming Growth Factor beta1 / metabolism
  • Up-Regulation
  • Ventricular Remodeling*
  • Young Adult

Substances

  • Biomarkers
  • Collagen Type III
  • Galectin 3
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta1
  • Monocrotaline
  • NADPH Oxidase 4
  • NOX4 protein, human
  • Nox4 protein, rat