Endothelin-1 upregulation mediates aging-related cardiac fibrosis

J Mol Cell Cardiol. 2015 Mar;80:101-9. doi: 10.1016/j.yjmcc.2015.01.001. Epub 2015 Jan 10.

Abstract

Endothelin-1 (ET-1) plays a major role in regulating myocardial fibrosis in several pathological conditions, such as hypertension and diabetes. Aging is an independent risk factor for myocardial fibrosis. We hypothesized that ET-1 upregulation may be a basis of enhanced collagen synthesis in the senescent fibroblasts resulting in cardiac fibrosis with aging. To examine this hypothesis, we cultured mouse cardiac fibroblasts to passage-30 (P30). β-Galactosidase activity and several other aging markers were markedly increased in P30 (vs. P3) fibroblasts, indicating that these cells were indeed undergoing senescence. Importantly, ET-1 expression was markedly upregulated in P30 (vs. P3) fibroblasts. Of note, estrogen receptor-α (ER-α), an important negative regulator of ET-1, was downregulated in P30 fibroblasts. We also studied aged (130-weeks old, female) mice hearts, and observed that ET-1 was upregulated and ER-α was downregulated in these hearts (vs. 6-week old mice hearts, female). Similar observations were made in the fibroblasts isolated from aged mice hearts. ET-1 upregulation with aging was also seen in ≈70-year old (vs. ≈30-year old) human heart sections. In concert with ET-1 upregulation, the expression of fibronectin and collagens was found to be markedly increased in P30 cardiac fibroblasts in culture, fibroblasts isolated from the aged mice hearts, and in aged human hearts. Interestingly, inhibition of ET-1 in the senescent P30 fibroblasts by 2 different strategies (the use of siRNA and the use of endothelin converting enzyme inhibitors) markedly suppressed expression of fibrosis signals. Further, treatment with synthetic ET-1 enhanced fibronectin and collagen expression in P3 cardiac fibroblasts. These observations in mice and human hearts suggest that aging-related cardiac fibrosis is, at least partially, dependent on the upregulation of ET-1.

Keywords: Aging; Cardiac fibrosis; Collagens; Endothelin-1; Fibronectin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / genetics*
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Aspartic Acid Endopeptidases / metabolism
  • Cellular Senescence / genetics
  • Endothelin-1 / genetics*
  • Endothelin-1 / metabolism
  • Endothelin-Converting Enzymes
  • Enzyme Activation
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibrosis
  • Gene Expression Regulation*
  • Gene Knockdown Techniques
  • Humans
  • Metalloendopeptidases / antagonists & inhibitors
  • Metalloendopeptidases / metabolism
  • Mice
  • Myocardium / metabolism*
  • Myocardium / pathology*
  • RNA Interference
  • Signal Transduction
  • Up-Regulation
  • beta-Galactosidase / metabolism

Substances

  • Endothelin-1
  • Estrogen Receptor alpha
  • beta-Galactosidase
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • Endothelin-Converting Enzymes