Co-expression of glycosylated aquaporin-1 and transcription factor NFAT5 contributes to aortic stiffness in diabetic and atherosclerosis-prone mice

J Cell Mol Med. 2020 Mar;24(5):2857-2865. doi: 10.1111/jcmm.14843. Epub 2020 Jan 22.

Abstract

Increased stiffness characterizes the early change in the arterial wall with subclinical atherosclerosis. Proteins inducing arterial stiffness in diabetes and hypercholesterolaemia are largely unknown. This study aimed at determining the pattern of protein expression in stiffening aorta of diabetic and hypercholesterolaemic mice. Male Ins2+/Akita mice were crossbred with ApoE-/- (Ins2+/Akita : ApoE-/- ) mice. Relative aortic distension (relD) values were determined by ultrasound analysis and arterial stiffness modulators by immunoblotting. Compared with age- and sex-matched C57/BL6 control mice, the aortas of Ins2+/Akita , ApoE-/- and Ins2+/Akita :ApoE-/- mice showed increased aortic stiffness. The aortas of Ins2+/Akita , ApoE-/- and Ins2+/Akita :ApoE-/- mice showed greater expression of VCAM-1, collagen type III, NADPH oxidase and iNOS, as well as reduced elastin, with increased collagen type III-to-elastin ratio. The aorta of Ins2+/Akita and Ins2+/Akita :ApoE-/- mice showed higher expression of eNOS and cytoskeletal remodelling proteins, such as F-actin and α-smooth muscle actin, in addition to increased glycosylated aquaporin (AQP)-1 and transcription factor NFAT5, which control the expression of genes activated by high glucose-induced hyperosmotic stress. Diabetic and hypercholesterolaemic mice have increased aortic stiffness. The association of AQP1 and NFAT5 co-expression with aortic stiffness in diabetes and hypercholesterolaemia may represent a novel molecular pathway or therapeutic target.

Keywords: arterial stiffening; cytoskeletal remodelling; diabetes; hypercholesterolaemia; hyperosmolarity; subclinical atherosclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aquaporin 1 / metabolism*
  • Atherosclerosis / metabolism*
  • Atherosclerosis / physiopathology*
  • Collagen Type III / metabolism
  • Cytoskeleton / metabolism
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / physiopathology*
  • Elastin / metabolism
  • Glycosylation
  • Male
  • Mice, Inbred C57BL
  • Muscle, Smooth / metabolism
  • NADPH Oxidases / metabolism
  • Nitric Oxide Synthase / metabolism
  • Phenotype
  • Protein Isoforms / metabolism
  • Transcription Factors / metabolism*
  • Vascular Cell Adhesion Molecule-1 / metabolism
  • Vascular Stiffness*

Substances

  • Collagen Type III
  • Nfat5 protein, mouse
  • Protein Isoforms
  • Transcription Factors
  • Vascular Cell Adhesion Molecule-1
  • Aquaporin 1
  • Elastin
  • Nitric Oxide Synthase
  • NADPH Oxidases