Atorvastatin regulates pericardial patch healing via the microRNA140-ADAM10-ephrinB2 pathway

Background: Pericardial patches are frequently used in vascular surgery to close arteriotomies. The early healing of these patches is mediated by attraction of CD34 and ephrinB2-positive cells. Atorvastatin is a commonly used statin drug that promotes healing of cardiovascular injury. We hypothesized that atorvastatin attracts ephrinB2-positive cells by regulating the microRNA140-ADAM10-ephrinB2 pathway during patch healing in the arterial environment. Methods: Pericardial patches were used to close an infra-renal aortic arteriotomy in Wistar rats (male, 200-400 g). Atorvastatin was given to rats at a daily dose of 0 mg, 2.5 mg, 5 mg or 10 mg. Patches were harvested at 1 or 4 weeks and analyzed by histology, immunohistochemistry, immunofluorescence, western blot and qPCR. Result: Animals treated with atorvastatin showed a higher number of infiltrating cells and a thicker patch neointima than the control animals. Furthermore, ADAM10 protein expression decreased (P<0.01) and ephrinB2 expression increased (P<0.01) in time- and atorvastatin dose-dependent manner. Similarly, ADAM10 mRNA expression decreased (P<0.01), while the expression of ephrinB2 mRNA and miR-140 mRNA expression increased (P<0.01; P<0.01) in a time- and dose-dependent manner. Conclusion: Atorvastatin regulates neointimal growth after pericardial patch angioplasty; atorvastatin is associated with infiltration of ephrinB2-positive cells, diminished ADAM10 expression, and increased ephrinB2 and miR-140 expression. These results suggest new mechanisms for regulating neointimal formation after vascular procedures. Clinical relevance: This study may help physicians to know more healing mechanism after pericardial patch angioplasty. Further, it may reveal some mechanism that how atorvastatin play roles in endothelium repair of the cardiovascular system.