Association of astragaloside IV-inhibited autophagy and mineralization in vascular smooth muscle cells with lncRNA H19 and DUSP5-mediated ERK signaling

Toxicol Appl Pharmacol. 2019 Feb 1:364:45-54. doi: 10.1016/j.taap.2018.12.002. Epub 2018 Dec 5.

Abstract

Defective autophagy in vascular smooth muscle cells (VSMCs) is the principal cause of atherosclerosis. This study aimed to investigate the effect of astragaloside IV (AS-IV) on VSMCs autophagy. In vivo, ApoE-/- mice were fed with high-fat diet ad libitum for eight weeks, with or without AS-IV (25 mg/kg, daily). In vitro, human VSMCs were cultured and treated with β-Glycerophosphate (10 mmol/L) and AS-IV (50 μg/ml). VSMCs autophagy, mineralization, expression of p-ERK1/2, p-mTOR, and autophagy-related proteins (LC3 II/I, p62, and Beclin 1) were detected. Increased autophagy and mineralization was observed in VSMCs in thoracic aorta of mice and in in vitro VSMCs model of atherosclerosis. AS-IV administration attenuated the autophagy and mineralization in VSMCs. Reverse expression profiles of H19 and DUSP5 were observed. AS-IV inhibited DUSP5 and autophagy-related proteins and increased expression of H19, level of p-ERK1/2 and p-mTOR. Further, autophagy and mineralization level in VSMCs were in line with DUSP5 expression level, but in contrast to H19, p-ERK1/2, and p-mTOR profiles. We demonstrated that AS-IV could attenuate autophagy and mineralization of VSMCs in atherosclerosis, which may be associated with H19 overexpression and DUSP5 inhibition.

Keywords: Astragaloside IV; Atherosclerosis; Autophagy; DUSP5; lncRNA H19.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / enzymology
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Autophagy / drug effects*
  • Autophagy-Related Proteins / metabolism
  • Cells, Cultured
  • Disease Models, Animal
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / enzymology
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / enzymology
  • Myocytes, Smooth Muscle / pathology
  • Phosphorylation
  • Plaque, Atherosclerotic
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Saponins / pharmacology*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Triterpenes / pharmacology*
  • Vascular Calcification / enzymology
  • Vascular Calcification / genetics
  • Vascular Calcification / pathology
  • Vascular Calcification / prevention & control*

Substances

  • Autophagy-Related Proteins
  • H19 long non-coding RNA
  • RNA, Long Noncoding
  • Saponins
  • Triterpenes
  • astragaloside A
  • MTOR protein, human
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • DUSP5 protein, human
  • Dual-Specificity Phosphatases
  • Dusp5 protein, mouse