TY - JOUR
T1 - Differential effect of zoledronic acid on human vascular smooth muscle cells
AU - Albadawi, Hassan
AU - Haurani, Mounir J.
AU - Oklu, Rahmi
AU - Trubiano, Jordan P.
AU - Laub, Peter J.
AU - Yoo, Hyung Jin
AU - Watkins, Michael T.
N1 - Funding Information:
The authors acknowledge funding from the National Institutes of Health ( 1R01AR055843 ), the American Diabetes Association , the Pacific Vascular Research Foundation and the Department of Surgery, Division of Vascular and Endovascular Surgery, Massachusetts General Hospital (the Geneen Fund). M.W. is a Ronnie Isenberg Scholar in Academic Surgery at the Massachusetts General Hospital.
PY - 2013/6/15
Y1 - 2013/6/15
N2 - Introduction: 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.
AB - Introduction: 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.
KW - Bisphosphonates
KW - Intimal hyperplasia
KW - Vascular smooth muscle
UR - http://www.scopus.com/inward/record.url?scp=84877705658&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84877705658&partnerID=8YFLogxK
U2 - 10.1016/j.jss.2012.10.033
DO - 10.1016/j.jss.2012.10.033
M3 - Article
C2 - 23164362
AN - SCOPUS:84877705658
SN - 0022-4804
VL - 182
SP - 339
EP - 346
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 2
ER -