J Lipid Atheroscler.  2019 Sep;8(2):267-276. 10.12997/jla.2019.8.2.267.

Anti-malarial Drugs Reduce Vascular Smooth Muscle Cell Proliferation via Activation of AMPK and Inhibition of Smad3 Signaling

Affiliations
  • 1Department of Pharmacology and Smart-Ageing Convergence Research Center, Yeungnam University College of Medicine, Daegu, Korea. changhoon_woo@yu.ac.kr

Abstract


OBJECTIVE
The aim of this study was to investigate the effects of 2 anti-malarial drugs, chloroquine (CQ) and hydroxychloroquine (HCQ), on inhibition of vascular smooth muscle cell (VSMC) proliferation both in vivo and in vitro via Adenosine monophosphate-activated protein kinase (AMPK) activation.
METHODS
Protein and mRNA levels were determined by western blot analysis and real-time reverse transcription-polymerase chain reaction in primary rat VSMCs treated with CQ and HCQ, respectively. Cell proliferation was measured by flow cytometry and cell counting. Mice carotid arteries were ligated and treated with CQ or HCQ every other day for 3 weeks. Pathological changes of carotid arteries were visualized by both microscopy and fluorescence microscopy.
RESULTS
CQ and HCQ increase AMPK phosphorylation in VSMCs. Both CQ and HCQ decrease platelet-derived growth factor-induced VSMC proliferation and cell cycle progression in an AMPK-dependent manner. In addition, CQ and HCQ inhibit Smad3 phosphorylation and VSMC proliferation induced by transforming growth factor-β1. Moreover, CQ and HCQ diminished neointimal proliferation in a mouse model of carotid artery ligation-induced neointima formation.
CONCLUSION
The results demonstrated that CQ and HCQ inhibit cell proliferation and cell cycle progression in VSMCs via the AMPK-dependent signaling pathway. Carotid artery ligation-induced intima thickness was reduced in mouse arteries treated with CQ or HCQ, suggesting a role for antimalarial drugs in treating atherosclerosis and restenosis.

Keyword

Chloroquine; Hydroxychloroquine; Vascular smooth muscle; AMP-activated protein kinase; Intima formation

MeSH Terms

Adenosine
AMP-Activated Protein Kinases*
Animals
Antimalarials
Arteries
Atherosclerosis
Blotting, Western
Carotid Arteries
Cell Count
Cell Cycle
Cell Proliferation*
Chloroquine
Flow Cytometry
Hydroxychloroquine
In Vitro Techniques
Mice
Microscopy
Microscopy, Fluorescence
Muscle, Smooth, Vascular*
Neointima
Phosphorylation
Protein Kinases
Rats
RNA, Messenger
AMP-Activated Protein Kinases
Adenosine
Antimalarials
Chloroquine
Hydroxychloroquine
Protein Kinases
RNA, Messenger
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