title: Differential effect of zoledronic acid on human vascular smooth muscle cells.
abstract: BACKGROUND
  The activation of human vascular smooth muscle cell proliferation, adhesion and migration is essential for intimal hyperplasia formation. These experiments were designed to test whether zoledronic acid (ZA) would modulate indices of human smooth muscle cell activation, exert differential effects on proliferating versus quiescent cells, and determine whether these effects were dependent on GTPase binding proteins prenylation. ZA was chosen for testing in these experiments because it is clinically used in humans with cancer, and has been shown to modulate rat smooth muscle cell proliferation and migration.
  
  
  METHODS
  Human aortic smooth muscle cells (HASMC) were cultured under either proliferating or growth arrest (quiescent) conditions in the presence or absence of ZA for 48 hours, whereupon the effect of ZA on HASMC proliferation, cellular viability, metabolic activity, and membrane integrity were compared. In addition, the effect of ZA on adhesion and migration were assessed in proliferating cells. The effect of increased concentration of ZA on the mevalonate pathway and genomic/cellular stress related poly-adenosine diphosphate ribose polymerase enzyme activity were assessed using the relative prenylation of Rap-1A/B protein and the formation of poly adenosine diphosphate-ribosylated protein, respectively.
  
  
  RESULTS
  There was a dose dependent inhibition of cellular proliferation, adhesion and migration following ZA treatment. ZA treatment decreased indices of cellular viability and significantly increased membrane injury in proliferating versus quiescent cells. This was correlated with the appearance of unprenylated Rap-1A protein and dose dependent down regulation of activity.
  
  
  CONCLUSIONS
  These data suggest that ZA is effective in inhibiting HASMC proliferation, adhesion, and migration, which coincide with the appearance of unprenylated RAP-1A/B protein, thereby suggesting that the mevalonate pathway may play a role in the inhibition of HASMC activation.
authors.affiliation: Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Hassan
authors.initials: H
authors.lastname: Albadawi
authors.forename: Mounir J
authors.initials: MJ
authors.lastname: Haurani
authors.forename: Rahmi
authors.initials: R
authors.lastname: Oklu
authors.forename: Jordan P
authors.initials: JP
authors.lastname: Trubiano
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Laub
authors.forename: Hyung-Jin
authors.initials: HJ
authors.lastname: Yoo
authors.forename: Michael T
authors.initials: MT
authors.lastname: Watkins
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D017368:Protein Prenylation / Q000187:drug effects; D000077211:Zoledronic Acid; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D000255:Adenosine Triphosphate; D020827:rap1 GTP-Binding Proteins