Thymosin Beta 4 protects mice from monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy

PLoS One. 2014 Nov 20;9(11):e110598. doi: 10.1371/journal.pone.0110598. eCollection 2014.

Abstract

Pulmonary hypertension (PH) is a progressive vascular disease of pulmonary arteries that impedes ejection of blood by the right ventricle. As a result there is an increase in pulmonary vascular resistance and pulmonary arterial pressure causing right ventricular hypertrophy (RVH) and RV failure. The pathology of PAH involves vascular cell remodeling including pulmonary arterial endothelial cell (PAEC) dysfunction and pulmonary arterial smooth muscle cell (PASMC) proliferation. Current therapies are limited to reverse the vascular remodeling. Investigating a key molecule is required for development of new therapeutic intervention. Thymosin beta-4 (Tβ4) is a ubiquitous G-actin sequestering protein with diverse biological function and promotes wound healing and modulates inflammatory responses. However, it remains unknown whether Tβ4 has any protective role in PH. The purpose of this study is to evaluate the whether Tβ4 can be used as a vascular-protective agent. In monocrotaline (MCT)-induced PH mouse model, we showed that mice treated with Tβ4 significantly attenuated the systolic pressure and RVH, compared to the MCT treated mice. Our data revealed for the first time that Tβ4 selectively targets Notch3-Col 3A-CTGF gene axis in preventing MCT-induced PH and RVH. Our study may provide pre-clinical evidence for Tβ4 and may consider as vasculo-protective agent for the treatment of PH induced RVH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Collagen Type III / genetics
  • Collagen Type III / metabolism
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / prevention & control*
  • Hypertrophy, Right Ventricular / chemically induced
  • Hypertrophy, Right Ventricular / pathology
  • Hypertrophy, Right Ventricular / prevention & control*
  • Injections, Intraperitoneal
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Mice
  • Monocrotaline / toxicity*
  • Receptor, Notch3
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Signal Transduction / drug effects
  • Thymosin / administration & dosage*
  • Thymosin / pharmacology

Substances

  • CCN2 protein, mouse
  • Collagen Type III
  • Notch3 protein, mouse
  • Receptor, Notch3
  • Receptors, Notch
  • Connective Tissue Growth Factor
  • thymosin beta(4)
  • Thymosin
  • Monocrotaline

Grant support

This study was partly supported by start-up funds from the Texas A & M Health Science Center, College of Medicine, by an American Heart Association- Grant-in-Aid (14GRNT 20490320), by Research Mentor Award by Scott & White Memorial Hospital and Texas A&M and Natural National Science Foundation of China to S. Gupta (SG) and Liling Wu. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.