Therapeutic manipulation of angiogenesis with miR-27b.

Abstract

Background: Multiple studies demonstrated pro-angiogenic effects of microRNA (miR)-27b. Its targets include Notch ligand Dll4, Sprouty (Spry)-2, PPARγ and Semaphorin (SEMA) 6A. miR-27 effects in the heart are context-dependent: although it is necessary for ventricular maturation, targeted overexpression in cardiomyocytes causes hypertrophy and dysfunction during development. Despite significant recent advances, therapeutic potential of miR-27b in cardiovascular disease and its effects in adult heart remain unexplored. Here, we assessed the therapeutic potential of miR-27b mimics and inhibitors in rodent models of ischemic disease and cancer.

Methods: We have used a number of models to demonstrate the effects of miR-27b mimicry and inhibition in vivo, including subcutaneous Matrigel plug assay, mouse models of hind limb ischemia and myocardial infarction and subcutaneous Lewis Lung carcinoma.

Results: Using mouse model of myocardial infarction due to the coronary artery ligation, we showed that miR-27b mimic had overall beneficial effects, including increased vascularization, decreased fibrosis and increased ejection fraction. In mouse model of critical limb ischemia, miR-27b mimic also improved tissue re-vascularization and perfusion. In both models, miR-27b mimic clearly decreased macrophage recruitment to the site of hypoxic injury. In contrast, miR-27b increased the recruitment of bone marrow derived cells to the neovasculature, as was shown using mice reconstituted with fluorescence-tagged bone marrow. These effects were due, at least in part, to the decreased expression of Dll4, PPARγ and IL10. In contrast, blocking miR-27b significantly decreased vascularization and reduced growth of subcutaneous tumors and decreased BMDCs recruitment to the tumor vasculature.

Conclusions: Our study demonstrates the utility of manipulating miR-27b levels in the treatment of cardiovascular disease and cancer.