CTGF/CCN2 is an autocrine regulator of cardiac fibrosis

J Mol Cell Cardiol. 2018 Aug;121:205-211. doi: 10.1016/j.yjmcc.2018.07.130. Epub 2018 Jul 21.

Abstract

Cardiac fibrosis is a common pathologic consequence of stress insult to the heart and is characterized by abnormal deposition of fibrotic extracellular matrix that compromises cardiac function. Cardiac fibroblasts are key mediators of fibrotic remodeling and are regulated by secreted stress-response proteins. The matricellular protein connective tissue growth factor (CTGF), or CCN2, is strongly produced by injured cardiomyocytes and although it is considered a pro-fibrotic factor in many organ systems, its role in cardiac fibrosis is controversial. Here we adopted a cell-specific genetic approach to conditionally delete CCN2 in either cardiomyocytes or activated fibroblasts. Fibrosis was induced by angiotensin II-based neurohumoral stimulation, an insult that strongly induces CCN2 expression from cardiomyocytes and to a lesser extent in fibroblasts. Remarkably, only CCN2 deletion from activated fibroblasts inhibited the fibrotic remodeling while deletion from cardiomyocytes (the main source of CCN2 in the heart) had no effects. In vitro experiments revealed that although efficiently secreted by both fibroblasts and cardiomyocytes, only fibroblast-derived CCN2 is proficient in its ability to fully activate fibroblasts. These results overall indicate that although secreted into the extracellular matrix, CCN2 acts in an autocrine fashion. Secretion of CCN2 by cardiomyocytes is not pro-fibrotic, while fibroblast-derived CCN2 can modulate fibrosis in the heart. In conclusion we found that cardiomyocyte-derived CCN2 is dispensable for cardiac fibrosis, while inhibiting CCN2 induction in activated fibroblasts is sufficient to abrogate the cardiac fibrotic response to angiotensin II. Hence, CCN2 is an autocrine factor in the heart.

Keywords: CCN2; CTGF; Cardiac fibrosis; Cardiomyocytes; Myofibroblasts.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin II / genetics*
  • Angiotensin II / metabolism
  • Animals
  • Autocrine Communication / genetics
  • Connective Tissue Growth Factor / genetics*
  • Connective Tissue Growth Factor / metabolism
  • Fibrosis / genetics*
  • Fibrosis / pathology
  • Heart Failure / genetics*
  • Heart Failure / pathology
  • Humans
  • Mice
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Ventricular Remodeling / genetics

Substances

  • Angiotensin II
  • Connective Tissue Growth Factor