Uric acid stimulates proliferative pathways in vascular smooth muscle cells through the activation of p38 MAPK, p44/42 MAPK and PDGFRβ

J Recept Signal Transduct Res. 2017 Apr;37(2):167-173. doi: 10.1080/10799893.2016.1203941. Epub 2016 Jul 12.

Abstract

Hyperuricemia and angiotensin II (Ang II) may have a pathogenetic role in the development of hypertension and atherosclerosis as well as cardiovascular disease (CVD) and its prognosis. The purpose of this study was to investigate whether uric acid can induce proliferative pathways of vascular smooth muscle cell (VSMC) that are thought to be responsible for the development of CVD. The phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), p44/42 mitogen-activated protein kinase (p44/42 MAPK) and platelet-derived growth factor receptor β (PDGFRβ) was measured by Elisa and Western blot techniques to determine the activation of proliferative pathways in primary cultured VSMCs from rat aorta. Results demonstrated that uric acid can stimulate p38 MAPK, p44/42 MAPK and PDGFRβ phosphorylation in a time- and concentration-dependent manner. Furthermore, treatment of VSMCs with the angiotensin II type I receptor (AT1R) inhibitor losartan suppressed p38 MAPK and p44/42 MAPK induction by uric acid. The stimulatory effect of uric acid on p38 MAPK was higher compared to that of Ang II. The results of this study show for the first time that uric acid-induced PDGFRβ phosphorylation plays a crucial role in the development of CVDs and that elevated uric acid levels could be a potential therapeutical target in CVD patients.

Keywords: Ang II; PDGFRβ; VSMC; p38 MAPK; p44/42 MAPK; uric acid.

MeSH terms

  • Angiotensin II / metabolism
  • Animals
  • Atherosclerosis / drug therapy
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Cardiovascular Diseases / drug therapy*
  • Cardiovascular Diseases / genetics
  • Cardiovascular Diseases / pathology
  • Cell Proliferation / drug effects
  • Gene Expression Regulation / drug effects
  • Humans
  • Hypertension / drug therapy
  • Hypertension / genetics
  • Hypertension / pathology
  • Hyperuricemia / drug therapy
  • Hyperuricemia / genetics
  • Losartan / administration & dosage
  • Mitogen-Activated Protein Kinase 3 / biosynthesis
  • Mitogen-Activated Protein Kinase 3 / genetics*
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Phosphorylation / drug effects
  • Rats
  • Receptor, Angiotensin, Type 1 / genetics*
  • Receptor, Angiotensin, Type 1 / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / biosynthesis*
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Uric Acid / administration & dosage
  • p38 Mitogen-Activated Protein Kinases / biosynthesis*
  • p38 Mitogen-Activated Protein Kinases / genetics

Substances

  • Receptor, Angiotensin, Type 1
  • Angiotensin II
  • Uric Acid
  • Receptor, Platelet-Derived Growth Factor beta
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • Losartan