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Cell-Specific Functions of ADAM17 Regulate the Progression of Thoracic Aortic Aneurysm

Mengcheng Shen1,2, Mei Hu1,2, Paul W M Fedak3,4

  • 1From the Department of Physiology (M.S., M.H., Z.K.).

Circulation Research
|June 23, 2018
PubMed
Abstract

Insights

A disintegrin and metalloproteinase-17 (ADAM17) plays a key role in thoracic aortic aneurysm (TAA) progression by affecting smooth muscle cells and endothelial cells. Inhibiting ADAM17 shows promise for treating TAA.

Area of Science:

  • Cardiovascular Biology
  • Protease Function
  • Aortic Disease Research

Background:

  • ADAM17 (a disintegrin and metalloproteinase-17) is a membrane-bound enzyme involved in proteolytic processing of transmembrane proteins.
  • ADAM17 is implicated in various pathologies, but its specific role in thoracic aortic aneurysm (TAA) pathogenesis was previously undetermined.

Purpose of the Study:

  • To investigate the cell-specific roles of vascular ADAM17 in the development and progression of TAA.
  • To determine if targeting ADAM17 could be a therapeutic strategy for TAA.

Main Methods:

  • Analysis of ADAM17 expression in human aneurysmal thoracic aorta.
  • Generation of mice with ADAM17 deficiency in smooth muscle cells (SMCs) or endothelial cells (ECs) to assess TAA progression in vivo.
  • In vitro studies using primary mouse and human SMCs and ECs to confirm cell-specific functions.
  • Administration of an ADAM17-selective inhibitor (PF-548) to evaluate therapeutic potential.

Main Results:

  • ADAM17 expression was elevated in the tunica media and intima of human aneurysmal aortas.
  • ADAM17 deficiency in either SMCs or ECs significantly suppressed TAA dilation and adverse remodeling in mice.
  • Loss of ADAM17 in SMCs prevented phenotypic switching and fibrosis, while loss in ECs preserved the intimal barrier integrity.
  • Inhibition of ADAM17, either before or after TAA induction, effectively prevented aneurysmal growth progression.

Conclusions:

  • ADAM17 exhibits distinct cell-specific functions in TAA, promoting pathological SMC remodeling and compromising EC barrier integrity.
  • Targeting ADAM17 in both SMCs and ECs offers a dual protective mechanism against TAA progression.
  • ADAM17 is a critical therapeutic target for TAA due to its significant impact on key cell types within the aortic wall.
Keywords:
aneurysmaortic aneurysm, thoracicaortic diseasesendothelial cellsinflammationmuscle, smooth, vascular

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