Long pentraxin PTX3 exacerbates pressure overload-induced left ventricular dysfunction

PLoS One. 2013;8(1):e53133. doi: 10.1371/journal.pone.0053133. Epub 2013 Jan 23.

Abstract

Background: Left ventricular hypertrophy is enhanced by an inflammatory state and stimulation of various cytokines. Pentraxin 3 (PTX3) is rapidly produced in response to inflammatory signals, and high plasma PTX3 levels are seen in patients with heart failure. This study aimed to examine the influence of PTX3 on cardiac hypertrophy and left ventricular dysfunction with respect to pressure overload.

Methods and results: PTX3 systemic knockout (PTX3-KO) mice, transgenic mice with cardiac-specific overexpression of PTX3 (PTX3-TG), and the respective wild-type (WT) littermate mice were subjected to transverse aortic constriction (TAC) or a sham operation. Cardiac PTX3 expression increased after TAC in WT mice. In vitro, hydrogen peroxide induced the expression of PTX3 in both cardiac myocytes and cardiac fibroblasts. Recombinant PTX3 phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) in cardiac fibroblasts. Phosphorylation of cardiac ERK1/2 and nuclear factor kappa-B after TAC was attenuated in the PTX3-KO mice but was enhanced in the PTX3-TG mice compared with WT mice. Interleukin-6 and connective tissue growth factor production was lower in the PTX3-KO mice than in the WT mice, but this was augmented in the PTX3-TG mice than in the WT mice. Echocardiography revealed that adverse remodeling with left ventricular dysfunction, as well as with increased interstitial fibrosis, was enhanced in PTX3-TG mice, while these responses were suppressed in PTX3-KO mice.

Conclusion: The local inflammatory mediator PTX3 directly modulates the hypertrophic response and ventricular dysfunction following an increased afterload.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / diagnostic imaging
  • Aorta / metabolism*
  • Aorta / pathology
  • C-Reactive Protein / genetics
  • C-Reactive Protein / metabolism*
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Constriction, Pathologic / genetics
  • Constriction, Pathologic / metabolism*
  • Constriction, Pathologic / pathology
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibrosis
  • Gene Expression Regulation / drug effects
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Hypertrophy, Left Ventricular / diagnostic imaging
  • Hypertrophy, Left Ventricular / genetics
  • Hypertrophy, Left Ventricular / metabolism*
  • Hypertrophy, Left Ventricular / pathology
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Mice
  • Mice, Transgenic
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Myofibroblasts / drug effects
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Phosphorylation
  • Signal Transduction / drug effects
  • Ultrasonography
  • Ventricular Dysfunction, Left / diagnostic imaging
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Dysfunction, Left / metabolism*
  • Ventricular Dysfunction, Left / pathology

Substances

  • CCN2 protein, mouse
  • Interleukin-6
  • NF-kappa B
  • Nerve Tissue Proteins
  • neuronal pentraxin
  • Connective Tissue Growth Factor
  • C-Reactive Protein
  • Hydrogen Peroxide
  • Extracellular Signal-Regulated MAP Kinases

Grants and funding

This study was supported in part by a grant-in-aid for Scientific Research (Nos. 19590804 and 21590935 to Y.T., 21590923 to I.K., and 21790701 and 23790830 to T.S.) from the Ministry of Education, Science, Sports, and Culture, Japan, and a grant-in-aid from the 21st Global Century Center of Excellence (COE) program of the Japan Society for the Promotion of Science. A.M. was supported by the Italian Ministry of Health and by the European Commission, Project Tolerage. Y.T. was supported by the Mitsubishi Pharma Research Foundation, Takeda Science Foundation, the Uehara Memorial Foundation, and Fukuda Foundation for Medical Technology. T.S. was supported by the Japan Heart Foundation Research Grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.