Peripheral Vascular Disease
In diabetic patients, large-calibre vessels show aggressive macrovascular atherosclerotic disease that accounts for ischaemic complications, including myocardial infarction, peripheral artery disease (PAD) and stroke. PAD can progress to critical limb ischaemia (CLI), a life-threatening condition characterized by pain at rest, tissue loss with ulceration and/or gangrene (Norgren et al. 2007). Once CLI occurs, blood flow (BF) must be restored by either percutaneous angioplasty (PTA) or surgical revascularization. If revascularisation is infeasible, then amputation is inevitable, and this outcome is far more common in diabetic patients (Faglia 2011). A recent report showed that miR-126, which is known to be highly expressed in endothelial cells where it positively regulates angiogenesis (Fish et al. 2008), is down- regulated in culture-selected PACs isolated from diabetic patients without vascular complications (Meng et al. 2012). In this respect, we have recently showed that culture-selected PACs generated from peripheral blood mononuclear cells (MNCs) of diabetic patients with CLI express increased levels of antiangiogenic miRNAs. Among those, miR-15a and miR-16 showed anti-migratory and pro-apoptotic activities on PACs. Interestingly, miR-15a and miR-16 were also abundantly present in PB CD34+ cells and other vascular cells and were packaged in cell-secreted exo- somes (Spinetti et al. 2013b). In Homo sapiens, two miR-15/16 clusters exist: miR- 15a/miR-16-1 and miR-15b/miR-16-2 (at 13q14.2 and 3q25.33, respectively). MiR-15a and miR-16 share a portion of their “seed” sequence (i.e. the sequence which binds to the 3’UTR region of the targeted mRNAs) with five other miRNAs, including miR-503 and miR-424 (Caporali and Emanueli 2012). We previously showed that miR-503 impairs angiogenesis in the setting of CLI and diabetes, by directly targeting the cell cycle regulators cyclin E1 and cdc25A (Caporali et al. 2011). Chamorro et al. demonstrated that miR-16 and miR-424 inhibit in vitro endothelial function and angiogenesis by modulating the expression of VEGF-A, KDR and FGF-R1 (fibroblast growth factor receptor-1) (Chamorro-Jorganes et al. 2011). Moreover, Hullinger et al. showed that inhibition of miR-15 protects against cardiac ischaemic injury (Hullinger et al. 2012).
Since miRNAs influence the therapeutic potential of human embryonic stem cell-derived endothelial progenitor cells and pericyte progenitor cells (Katare et al. 2011a; Kane et al. 2012) upon their transplantation in mouse models of peripheral or myocardial ischaemia, it may be feasible in the future to intervene at the miRNA level to augment PAC regenerative potential. In fact, therapeutic stimulation of angiogenesis represents a strategy to support postischaemic BF recovery, wound closure and tissue regeneration. Despite the encouraging evidence from early clinical trials (Assmus et al. 2002; Fadini et al. 2009; Gupta and Losordo 2011; Amann et al. 2008; Sprengers et al. 2010), the regenerative potential of proangiogenic cells derived from patients with either diabetes or tissue ischaemia is reduced, and the underpinning molecular mechanisms have not been clarified (Fadini et al. 2006; Vasa et al. 2001; Heeschen et al. 2004).
A summary of the outcomes of miRNA dysregulation in diabetic cardiac disease and limb ischaemia is found in Fig. 3.1.
- 3 MicroRNAs in Diabetes and Its Vascular Complications
Fig. 3.1 Dysfunction of microRNAs in diabetic cardiovascular disease