Effects of a dammarane-type saponin, ginsenoside Rd, in nicotine-induced vascular endothelial injury

Phytomedicine. 2020 Dec:79:153325. doi: 10.1016/j.phymed.2020.153325. Epub 2020 Sep 1.

Abstract

Background: Panax notoginseng (Burk.) F.H. Chen is a traditional medicinal plant widely used to prevent and treat cardiovascular diseases. Ginsenoside Rd (GRd) is a major bioactive component of P. notoginseng, but specific effects on cardiovascular disease-related pathogenic processes are rarely studied, especially vascular endothelial injury.

Purpose: This study investigated the potential protective efficacy of GRd against nicotine-induced vascular endothelial cell injury, disruption of vascular nitric oxide (NO) signaling, aberrant endothelium-monocyte adhesion, platelet aggregation, and vasoconstriction.

Study design/methods: Vascular endothelial injury and functional disruption were investigated in cultured human umbilical vein endothelial cells (HUVECs) by biochemical assays for nitric oxide (NO) and angiotensin II (Ang II), immunofluorescence (IF) and western blotting for expression analyses of apoptosis- related proteins, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), Ang II type receptor 1 (AGTR1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB). In addition, vascular protection by GRd was examined in nicotine-administered Sprague-Dawley (SD) rats by serum NO and Ang II assays, and by hematoxylin-eosin (HE) and immunostaining of aorta. We also examined effects of GRd on monocyte (THP-1 cells) adhesion assays, adenosine diphosphate (ADP)-induced platelet aggregation, and phenylephrine (PE)-induced vasoconstriction of isolated rat aortic rings.

Results: In HUVECs, nicotine significantly suppressed NO production, enhanced Ang II production, downregulated eNOS expression, and upregulated expression levels of AGTR1, TLR4, MyD88, NF-κB, iNOS, Bax/Bcl-2 ratio, cleaved caspase-3, and cytochrome c (cyt c). All of these changes were significantly reversed by GRd. In rats, oral GRd reversed the reduction NO and enhanced Ang II production in serum induced by nicotine administration, and HE staining revealed protection of aortic endothelial cells. In addition, GRd reversed nicotine-mediated enhancement of HUVECs-monocyte adhesion, inhibited ADP-induced platelet aggregation and PE-induced vasoconstriction.

Conclusion: GRd may prevent nicotine-induced cardiovascular diseases by preserving normal vascular endothelial NO signaling, suppressing platelet aggregation and vasoconstriction, and by preventing endothelial cell-monocyte adhesion.

Keywords: Ginsenoside Rd; Huvecs; NO; Nicotine; Platelet aggregation.

MeSH terms

  • Angiotensin II / blood
  • Angiotensin II / metabolism
  • Animals
  • Aorta / drug effects
  • Dammaranes
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Ginsenosides / chemistry
  • Ginsenosides / pharmacology*
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Male
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / metabolism
  • Nicotine / toxicity*
  • Nitric Oxide / blood
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Phenylephrine / pharmacology
  • Platelet Aggregation / drug effects
  • Rats, Sprague-Dawley
  • Receptor, Angiotensin, Type 1 / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Triterpenes / chemistry
  • Vasoconstriction / drug effects

Substances

  • AGTR1 protein, human
  • Ginsenosides
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Receptor, Angiotensin, Type 1
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Triterpenes
  • Angiotensin II
  • Phenylephrine
  • Nitric Oxide
  • Nicotine
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • ginsenoside Rd