A disintegrin and metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis

Am J Physiol Heart Circ Physiol. 2020 Feb 1;318(2):H238-H251. doi: 10.1152/ajpheart.00496.2019. Epub 2019 Nov 27.

Abstract

A disintegrin and metalloproteinase (ADAM)12 is considered to promote cardiac dysfunction based on the finding that a small-molecule ADAM12 inhibitor, KB-R7785, ameliorated cardiac function in a transverse aortic constriction (TAC) model by inhibiting the proteolytic activation of heparin-binding-EGF signaling. However, this compound has poor selectivity for ADAM12, and the role of ADAM12 in cardiac dysfunction has not yet been investigated using genetic loss-of-function mice. We revealed that ADAM12 knockout mice showed significantly more advanced cardiac hypertrophy and higher mortality rates than wild-type mice 4 wk after TAC surgery. An ADAM12 deficiency resulted in significantly more expanded cardiac fibrosis accompanied by increased collagen-related gene expression in failing hearts. The results of a genome-wide transcriptional analysis suggested a strongly enhanced focal adhesion- and fibrosis-related signaling pathway in ADAM12 knockout hearts. The loss of ADAM12 increased the abundance of the integrinβ1 subunit and transforming growth factor (TGF)-β receptor types I and III, and this was followed by the phosphorylation of focal adhesion kinase, Akt, mammalian target of rapamycin, ERK, and Smad2/3 in the heart, which resulted in cardiac dysfunction. The present results revealed that the loss of ADAM12 enhanced focal adhesion and canonical TGF-β signaling by regulating the abundance of the integrinβ1 and TGF-β receptors.NEW & NOTEWORTHY In contrast to a long-believed cardio-damaging role of a disintegrin and metalloproteinase (ADAM)12, cardiac hypertrophy was more severe, cardiac function was lower, and mortality was higher in ADAM12 knockout mice than in wild-type mice after transverse aortic constriction surgery. The loss of ADAM12 enhanced focal adhesion- and fibrosis-related signaling pathways in the heart, which may compromise cardiac function. These results provide insights for the development of novel therapeutics that target ADAM12 to treat heart failure.

Keywords: ADAM12; cardiac hypertrophy; fibrosis; focal adhesion.

MeSH terms

  • ADAM12 Protein / antagonists & inhibitors
  • ADAM12 Protein / drug effects
  • ADAM12 Protein / genetics*
  • Animals
  • Blood Pressure
  • Cardiomegaly / prevention & control*
  • Disintegrins / therapeutic use*
  • Fibrosis
  • Focal Adhesions / drug effects
  • Heart Failure / prevention & control*
  • Integrin beta1 / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / pathology*
  • Receptors, Transforming Growth Factor beta / drug effects
  • Receptors, Transforming Growth Factor beta / genetics
  • Signal Transduction / drug effects

Substances

  • Disintegrins
  • Integrin beta1
  • Receptors, Transforming Growth Factor beta
  • ADAM12 Protein
  • Adam12 protein, mouse