Melatonin attenuates angiotensin II-induced abdominal aortic aneurysm through the down-regulation of matrix metalloproteinases

Oncotarget. 2017 Feb 28;8(9):14283-14293. doi: 10.18632/oncotarget.15093.

Abstract

Abdominal aortic aneurysm (AAA) affects more than 5% of the population in developed countries and the pharmacotherapies for AAA are limited. Here, we explored whether melatonin regulates the development of AAA. In smooth muscle cells, melatonin treatment decreases angiotensin II-induced matrix metalloproteinase 2 (MMP2) and MMP9 expression. Human antigen R (HuR) could bind with the adenylateuridylate-rich elements of MMP2 and MMP9 mRNAs 3' untranslated region, resulting in the increased stability of MMP2 and MMP9 mRNAs. HuR is required for angiotensin II-induced MMP2 and MMP9 expression. Moreover, melatonin suppresses angiotensin II-induced HuR expression through inhibiting NF-κB signaling, leading to decreased MMP2 and MMP9 levels. Finally, melatonin attenuates the development of AAA in ApoE-/- mice infused with angiotensin II in vivo. These data support a role of HuR in the development of AAA and possible therapeutic roles for melatonin and/or HuR inhibition in AAA.

Keywords: HuR; MMP2; MMP9; Pathology Section; abdominal aortic aneurysm; melatonin.

MeSH terms

  • Angiotensin II / toxicity*
  • Animals
  • Antioxidants / pharmacology
  • Aortic Aneurysm, Abdominal / chemically induced
  • Aortic Aneurysm, Abdominal / drug therapy*
  • Aortic Aneurysm, Abdominal / metabolism
  • Apolipoproteins E / physiology*
  • Blotting, Western
  • Cells, Cultured
  • Disease Models, Animal
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Male
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase 9 / metabolism*
  • Melatonin / pharmacology*
  • Mice
  • Mice, Knockout
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction

Substances

  • Antioxidants
  • Apolipoproteins E
  • RNA, Messenger
  • Angiotensin II
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Melatonin