title: AdipoRon, an adiponectin receptor agonist, attenuates PDGF-induced VSMC proliferation through inhibition of mTOR signaling independent of AMPK: Implications toward suppression of neointimal hyperplasia.
abstract: Hypoadiponectinemia is associated with an increased risk of coronary artery disease. Although adiponectin replenishment mitigates neointimal hyperplasia and atherosclerosis in mouse models, adiponectin therapy has been hampered in a clinical setting due to its large molecular size. Recent studies demonstrate that AdipoRon (a small-molecule adiponectin receptor agonist) improves glycemic control in type 2 diabetic mice and attenuates postischemic cardiac injury in adiponectin-deficient mice, in part, through activation of AMP-activated protein kinase (AMPK). To date, it remains unknown as to whether AdipoRon regulates vascular smooth muscle cell (VSMC) proliferation, which plays a major role in neointima formation. In the present study, oral administration of AdipoRon (50mg/kg) in C57BL/6J mice significantly diminished arterial injury-induced neointima formation by ∼57%. Under in vitro conditions, AdipoRon treatment led to significant inhibition of platelet-derived growth factor (PDGF)-induced VSMC proliferation, DNA synthesis, and cyclin D1 expression. While AdipoRon induced a rapid and sustained activation of AMPK, it also diminished basal and PDGF-induced phosphorylation of mTOR and its downstream targets, including p70S6K/S6 and 4E-BP1. However, siRNA-mediated AMPK downregulation showed persistent inhibition of p70S6K/S6 and 4E-BP1 phosphorylation, indicating AMPK-independent effects for AdipoRon inhibition of mTOR signaling. In addition, AdipoRon treatment resulted in a sustained and transient decrease in PDGF-induced phosphorylation of Akt and ERK, respectively. Furthermore, PDGF receptor-β tyrosine phosphorylation, which controls the phosphorylation state of Akt and ERK, was diminished upon AdipoRon treatment. Together, the present findings suggest that orally-administered AdipoRon has the potential to limit restenosis after angioplasty by targeting mTOR signaling independent of AMPK activation.
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Arwa
authors.initials: A
authors.lastname: Fairaq
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Noha M
authors.initials: NM
authors.lastname: Shawky
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Islam
authors.initials: I
authors.lastname: Osman
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Prahalathan
authors.initials: P
authors.lastname: Pichavaram
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA; Vascular Biology Center, Department of Pharmacology and Toxicology, Augusta University, Augusta, GA, USA; Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA. Electronic address: lsegar@augusta.edu.
authors.forename: Lakshman
authors.initials: L
authors.lastname: Segar
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058426:Neointima / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000627:therapeutic use*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D054419:Receptors, Adiponectin / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C585113:AdipoRon; D010880:Piperidines; D010982:Platelet-Derived Growth Factor; D054419:Receptors, Adiponectin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; AdipoRon; Arterial injury; PDGF; Vascular smooth muscle cells; mTOR