Dose-dependent effect of pitavastatin on VEGF and angiogenesis in a mouse model of choroidal neovascularization.
OBJECTIVE
To evaluate the relation between statin therapy, vascular endothelial growth factor (VEGF) expression, vascular leakage, and CNV size in experimentally induced choroidal neovascularization (CNV).


METHODS
Wild-type (C57 Bl/6J) mice received pitavastatin 0.18 mg/kg per day (group 1), 1.8 mg/kg per day (group 2) or 18 mg/kg per day (group 3) for 3 days before laser-induced CNV and continued to receive the drug for 14 days. Serum total cholesterol levels were measured by spectrophotometry. Fluorescein angiograms were graded by masked observers. VEGF protein levels from retinal lysates were measured and CNV area was assessed by histology.


RESULTS
Pitavastatin did not reduce total serum cholesterol at any of the doses used. The incidence rate ratios for development of clinically significant CNV leakage was 0.62 (95% CI, 0.46-0.84) for group 1, 0.56 (95% CI, 0.28-1.10) for group 2, and 1.22 (95% CI, 1.01-1.48) for group 3 (P=0.002, 0.09, and 0.04, respectively). Mean CNV area increased by 13%, 22%, and 95% in groups 1, 2, and 3, respectively (P>0.05). Normalized VEGF levels did not mirror the observed changes in fluorescein leakage and CNV area in histologic examination.


CONCLUSIONS
Pitavastatin therapy for experimental CNV in wild-type mice resulted in reduced fluorescein leakage at a dose of 0.18 mg/kg per day. The higher dose of 18 mg/kg per day resulted in increased fluorescein leakage and a trend toward an increase in CNV size, indicating a potentiating effect in choroidal neovascular disease.
Zambarakji
Hadi J
HJ
Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston 02114, USA.
Nakazawa
Toru
T
Connolly
Edward
E
Lane
Anne Marie
AM
Mallemadugula
Sreedevi
S
Kaplan
Michael
M
Michaud
Norman
N
Hafezi-Moghadam
Ali
A
Gragoudas
Evangelos S
ES
Miller
Joan W
JW
D000818:Animals; D002784:Cholesterol / Q000097:blood; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D019793:Fluorescein / Q000378:metabolism; D005451:Fluorescein Angiography; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D011804:Quinolines / Q000008:administration & dosage*; D012160:Retina / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D002784:Cholesterol; C108475:pitavastatin; D019793:Fluorescein