Berberine attenuates pulmonary arterial hypertension via protein phosphatase 2A signaling pathway both in vivo and in vitro

J Cell Physiol. 2018 Dec;233(12):9750-9762. doi: 10.1002/jcp.26940. Epub 2018 Aug 5.

Abstract

Excessive proliferation, migration, and antiapoptosis of pulmonary artery (PA) smooth muscle cells (PASMCs) underlies the development of pulmonary vascular remodeling. The innervation of the PA is predominantly sympathetic, and increased levels of circulating catecholamines have been detected in pulmonary arterial hypertension (PAH), suggesting that neurotransmitters released by sympathetic overactivation may play an essential role in PAH. However, the responsible mechanism remains unclear. Here, to investigate the effects of norepinephrine (NE) on PASMCs and the related mechanism, we used 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, the proliferating cell nuclear antigen and the cell counting kit-8 assay to evaluate the proliferation of PASMCs, Boyden chamber migration, and wound-healing assays to assess migration and western blot analysis to investigate protein expression. We demonstrated that the phosphorylation level of the protein phosphatase 2A (PP2A) catalytic subunit (Y307) was higher in PAH patients and PAH models than in controls, both in vivo and in vitro. In addition, NE induced the proliferation and migration of PASMCs, which was attenuated by berberine (BBR), a Chinese herbal medicine, and/or PP2A overexpression. PP2A inhibition worsened NE-induced PAH and could not be reversed by BBR. Thus, PP2A is critical in driving PAH, and BBR may alleviate PAH via PP2A signaling pathways, thereby offering a potential therapeutic option for PAH.

Keywords: norepinephrine; protein phosphatase 2A; pulmonary arterial hypertension; pulmonary artery smooth muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Berberine / administration & dosage*
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Humans
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / pathology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / pathology
  • Norepinephrine / toxicity
  • Protein Phosphatase 2 / genetics*
  • Pulmonary Artery / drug effects*
  • Pulmonary Artery / pathology
  • Rats
  • Signal Transduction / drug effects
  • Vascular Remodeling / drug effects
  • Vascular Remodeling / genetics

Substances

  • Berberine
  • Protein Phosphatase 2
  • Norepinephrine