Critical limb ischemia (CLI), foot ulcers, former amputation, and impaired regeneration are independent risk factors for limb amputation in subjects with diabetes. The present work investigates whether and by which mechanism diabetes negatively impacts on functional properties of muscular pericytes (MPs), which are resident stem cells committed to reparative angiomyogenesis. We obtained muscle biopsy samples from patients with diabetes who were undergoing major limb amputation and control subjects. Diabetic muscles collected at the rim of normal tissue surrounding the plane of dissection showed myofiber degeneration, fat deposition, and reduction of MP vascular coverage. Diabetic MPs (D-MPs) display ultrastructural alterations, a differentiation bias toward adipogenesis at the detriment of myogenesis and an inhibitory activity on angiogenesis. Furthermore, they have an imbalanced redox state, with downregulation of the antioxidant enzymes superoxide dismutase 1 and catalase, and activation of the pro-oxidant protein kinase C isoform beta-II (PKC beta II)dependent p66(Shc) signaling pathway. A reactive oxygen species scavenger or, even more effectively, clinically approved PKC beta II inhibitors restore D-MP angiomyogenic activity. Inhibition of the PKC beta II-dependent p66(Shc) signaling pathway could represent a novel therapeutic approach for the promotion of muscle repair in individuals with diabetes.

Vono, R., Fuoco, C., Testa, S., Pirro, S., Maselli, D., Mccollough, D.f., et al. (2016). Activation of the pro-oxidant PKCβIIp66Shc Signaling pathway contributes to pericyte dysfunction in skeletal muscles of patients with diabetes with critical limb Ischemia. DIABETES, 65(12), 3691-3704 [10.2337/db16-0248].

Activation of the pro-oxidant PKCβIIp66Shc Signaling pathway contributes to pericyte dysfunction in skeletal muscles of patients with diabetes with critical limb Ischemia

Fuoco C.;Pirro S.;Maselli D.;Cesareni G.;Cannata S.;Gargioli C.
;
2016-09-06

Abstract

Critical limb ischemia (CLI), foot ulcers, former amputation, and impaired regeneration are independent risk factors for limb amputation in subjects with diabetes. The present work investigates whether and by which mechanism diabetes negatively impacts on functional properties of muscular pericytes (MPs), which are resident stem cells committed to reparative angiomyogenesis. We obtained muscle biopsy samples from patients with diabetes who were undergoing major limb amputation and control subjects. Diabetic muscles collected at the rim of normal tissue surrounding the plane of dissection showed myofiber degeneration, fat deposition, and reduction of MP vascular coverage. Diabetic MPs (D-MPs) display ultrastructural alterations, a differentiation bias toward adipogenesis at the detriment of myogenesis and an inhibitory activity on angiogenesis. Furthermore, they have an imbalanced redox state, with downregulation of the antioxidant enzymes superoxide dismutase 1 and catalase, and activation of the pro-oxidant protein kinase C isoform beta-II (PKC beta II)dependent p66(Shc) signaling pathway. A reactive oxygen species scavenger or, even more effectively, clinically approved PKC beta II inhibitors restore D-MP angiomyogenic activity. Inhibition of the PKC beta II-dependent p66(Shc) signaling pathway could represent a novel therapeutic approach for the promotion of muscle repair in individuals with diabetes.
6-set-2016
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/13 - BIOLOGIA APPLICATA
English
Aged; Blotting, Western; Cell Proliferation; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Human Umbilical Vein Endothelial Cells; Humans; Immunohistochemistry; In Vitro Techniques; Ischemia; Male; Microscopy, Electron, Transmission; Muscle, Skeletal; Oxidative Stress; Pericytes; Phthalimides; Protein Kinase C beta; Reactive Oxygen Species; Signal Transduction
Vono, R., Fuoco, C., Testa, S., Pirro, S., Maselli, D., Mccollough, D.f., et al. (2016). Activation of the pro-oxidant PKCβIIp66Shc Signaling pathway contributes to pericyte dysfunction in skeletal muscles of patients with diabetes with critical limb Ischemia. DIABETES, 65(12), 3691-3704 [10.2337/db16-0248].
Vono, R; Fuoco, C; Testa, S; Pirro, S; Maselli, D; Mccollough, Df; Sangalli, E; Pintus, G; Giordo, R; Finzi, G; Sessa, F; Cardani, R; Gotti, A; Losa, S; Cesareni, G; Rizzi, R; Bearzi, C; Cannata, S; Spinetti, G; Gargioli, C; Madeddu, P
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/241662
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