Statins have different effects beyond
cholesterol reduction and stimulate angiogenesis. We investigated the effect of
simvastatin in diabetes-related healing defects. An incisional skin
wound model produced on the back of female diabetic mice (db(+)/db(+)) and their normoglycemic littermates (db(+)/(+)m) was used. Animals were treated daily either with
simvastatin (5 mg/(kgi.p.)) or vehicle. Mice were killed on different days (3, 6 and 12 after skin injury) for measurement of
vascular endothelial growth factor (
VEGF)
mRNA and
protein expression, to assess histologically the healing process and to evaluate
wound breaking strength and angiogenesis by CD31 immunostaining.
Simvastatin administration in diabetic mice increased
VEGF mRNA (
simvastatin=4.8+/-0.6n-fold/
beta-actin; vehicle=2.3+/-0.4n-fold/
beta-actin) and
protein expression (
simvastatin=5+/-0.7 integrated intensity; vehicle=2.2+/-0.3 integrated intensity) and enhanced
nitric oxide wound content at day 6. Additionally, the
statin augmented breaking strength and
PECAM-1 immunostaining at day 12. Finally,
simvastatin administration restored the impaired wound healing process in diabetic mice. Similar results were obtained in normoglycaemic mice. Passive immunization with anti-
VEGF antibody (10 microg/mouse) completely abrogated the beneficial effects of
simvastatin on healing in diabetic mice.
Simvastatin has potential application in diabetes-related wound healing disorders.