Influence of atorvastatin on angiotensin I metabolism in resting and TNF-α -activated rat vascular smooth muscle cells

J Renin Angiotensin Aldosterone Syst. 2014 Dec;15(4):378-83. doi: 10.1177/1470320313475907. Epub 2013 Feb 6.

Abstract

Introduction: Vascular smooth muscle cells (VSMCs) are essential for maintaining vasculature homeostasis and function. By influence on its growth and activation both proinflammatory cytokines and peptides of the renin-angiotensin system (RAS) are potent regulators of VSMCs. Interestingly, angiotensin (Ang) II and Ang-(1-7) elicit opposite effects on VSMC activation, differentiation and proliferation. It has been suggested that statins, besides anti-inflammatory effects, may also modulate VSMC activation by their influence on the RAS.

Methods: The effect of atorvastatin on Ang I metabolism in a culture of explanted rat VSMCs was examined by liquid chromatography-mass spectrometry (LC-MS); expression of mRNA of the main RAS enzymes in VSMC was assessed by real-time polymerase chain reaction (PCR).

Results: In VSMC culture Ang-(1-7) was identified as a major product of Ang I metabolism. In this setting, TNF-α (1 ng/ml) caused a decrease in the conversion of Ang I to Ang-(1-7). This effect was accompanied by a decrease of mRNA expression of neutral endopeptidase (NEP) and angiotensin converting enzyme 2 (ACE2) and increase of mRNA of ACE. Interestingly, atorvastatin (3 μM) attenuated the effects of TNF-α on Ang-(1-7) production as well as reversed the influence of TNF-α on ACE and ACE2 expression.

Conclusions: Enhancement by atorvastatin of the ACE2/Ang-(1-7) axis in VSMCs could represent a new and beneficial mechanism on cardiovascular action of this widely used drug.

Keywords: Angiotensin; angiotensin converting enzyme; renin; statin; vascular smooth muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / metabolism*
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Atorvastatin
  • Heptanoic Acids / pharmacology*
  • Muscle, Smooth, Vascular / cytology*
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism*
  • Neprilysin / metabolism
  • Peptidyl-Dipeptidase A / metabolism
  • Pyrroles / pharmacology*
  • Rats, Wistar
  • Rest
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Heptanoic Acids
  • Pyrroles
  • Tumor Necrosis Factor-alpha
  • Angiotensin I
  • Atorvastatin
  • Peptidyl-Dipeptidase A
  • Ace2 protein, rat
  • Angiotensin-Converting Enzyme 2
  • Neprilysin