Spinetti, Gaia and Fortunato, Orazio and Caporali, Andrea and Shantikumar, Saran and Marchetti, Micol and Meloni, Marco and Descamps, Betty and Floris, Ilaria and Sangalli, Elena and Vono, Rosa and Faglia, Ezio and Specchia, Claudia and Pintus, Gianfranco and Madeddu, Paolo Roberto and Emanueli, Costanza (2013) MicroRNA-15a and microRNA-16 impair human circulating proangiogenic cell functions and are increased in the proangiogenic cells and serum of patients with critical limb ischemia. Circulation Research, Vol. 112 (2), p. 335-346. eISSN 1524-4571. Article.
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Rationale: Circulating proangiogenic cells (PACs) support postischemic neovascularization. Cardiovascular disease and diabetes mellitus impair PAC regenerative capacities via molecular mechanisms that are not fully known. We hypothesize a role for microRNAs (miRs). Circulating miRs are currently investigated as potential diagnostic and prognostic biomarkers.
Objective: The objectives were the following: to profile miR expression in PACs from critical limb ischemia (CLI) patients; to demonstrate that miR-15a and miR-16 regulate PAC functions; and to characterize circulating miR-15a and miR-16 and to investigate their potential biomarker value.
Methods and Results: Twenty-eight miRs potentially able to modulate angiogenesis were measured in PACs from CLI patients with and without diabetes mellitus and controls. miR-15a and miR-16 were further analyzed. CLI-PACs expressed higher level of mature miR-15a and miR-16 and of the primary transcript pri–miR-15a/16-1. miR-15a/16 overexpression impaired healthy PAC survival and migration. Conversely, miR-15a/16 inhibition improved CLI-PAC–defective migration. Vascular endothelial growth factor-A and AKT-3 were validated as direct targets of the 2 miRs, and their protein levels were reduced in miR-15a/16–overexpressing healthy PACs and in CLI-PACs. Transplantation of healthy PACs ex vivo–engineered with anti–miR-15a/16 improved postischemic blood flow recovery and muscular arteriole density in immunodeficient mice. miR-15a and miR-16 were present in human blood, including conjugated to argonaute-2 and in exosomes. Both miRs were increased in the serum of CLI patients and positively correlated with amputation after restenosis at 12 months postrevascularization of CLI type 2 diabetes mellitus patients. Serum miR-15a additionally correlated with restenosis at follow-up.
Conclusions: Ex vivo miR-15a/16 inhibition enhances PAC therapeutic potential, and circulating miR-15a and miR-16 deserves further investigation as a prognostic biomarker in CLI patients undergoing revascularization.
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