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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

Research output: Contribution to journalArticle (Academic Journal)

  • Gaia Spinetti
  • Orazio Fortunato
  • Andrea Caporali
  • Saran Shantikumar
  • Micol Marchetti
  • Marco Meloni
  • Betty Descamps
  • Ilaria Floris
  • Elena Sangalli
  • Rosa Vono
  • Ezio Faglia
  • Claudia Specchia
  • Gianfranco Pintus
  • Paolo Madeddu
  • Costanza Emanueli
Original languageEnglish
Pages (from-to)335-346
Number of pages38
JournalCirculation Research
Volume112
Issue number2
Early online date11 Dec 2012
DOIs
DateE-pub ahead of print - 11 Dec 2012
DatePublished (current) - 18 Jan 2013

Abstract

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: (1) to profile miR expression in PACs from critical limb ischemia (CLI) patients; (2) to demonstrate that miR-15a and miR-16 regulate PAC functions; and (3) 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. miR15a/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. (Circ Res. 2013;112:335-346.)

    Research areas

  • angiogenesis, diabetes mellitus, ischemia, microRNAs, microRNA-15a, microRNA-16, proangiogenic cells, ENDOTHELIAL PROGENITOR CELLS, EMBRYONIC STEM-CELLS, INHIBITS ANGIOGENESIS, MYOCARDIAL-INFARCTION, MONONUCLEAR-CELLS, GROWTH-FACTOR, NEOVASCULARIZATION, DISEASE, DIFFERENTIATION, TRANSPLANTATION

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