AIMS/HYPOTHESIS: Benfotiamine, a vitamin B1 analogue, reportedly prevents diabetic microangiopathy. The aim of this study was to evaluate whether benfotiamine is of benefit in reparative neovascularisation using a type I diabetes model of hindlimb ischaemia. We also investigated the involvement of protein kinase B (PKB)/Akt in the therapeutic effects of benfotiamine. METHODS: Streptozotocin-induced diabetic mice, given oral benfotiamine or vehicle, were subjected to unilateral limb ischaemia. Reparative neovascularisation was analysed by histology. The expression of Nos3 and Casp3 was evaluated by real-time PCR, and the activation state of PKB/Akt was assessed by western blot analysis and immunohistochemistry. The functional importance of PKB/Akt in benfotiamine-induced effects was investigated using a dominant-negative construct. RESULTS: Diabetic muscles showed reduced transketolase activity, which was corrected by benfotiamine. Importantly, benfotiamine prevented ischaemia-induced toe necrosis, improved hindlimb perfusion and oxygenation, and restored endothelium-dependent vasodilation. Histological studies revealed the improvement of reparative neovascularisation and the inhibition of endothelial and skeletal muscle cell apoptosis. In addition, benfotiamine prevented the vascular accumulation of advanced glycation end products and the induction of pro-apoptotic caspase-3, while restoring proper expression of Nos3 and Akt in ischaemic muscles. The benefits of benfotiamine were nullified by dominant-negative PKB/Akt. In vitro, benfotiamine stimulated the proliferation of human EPCs, while inhibiting apoptosis induced by high glucose. In diabetic mice, the number of circulating EPCs was reduced, with the deficit being corrected by benfotiamine. CONCLUSIONS/ INTERPRETATION: We have demonstrated, for the first time, that benfotiamine aids the post-ischaemic healing of diabetic animals via PKB/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis. In addition, benfotiamine combats the diabetes-induced deficit in endothelial progenitor cells.
AIMS/HYPOTHESIS: Benfotiamine, a vitamin B1 analogue, reportedly prevents diabetic microangiopathy. The aim of this study was to evaluate whether benfotiamine is of benefit in reparative neovascularisation using a type I diabetes model of hindlimb ischaemia. We also investigated the involvement of protein kinase B (PKB)/Akt in the therapeutic effects of benfotiamine. METHODS:Streptozotocin-induced diabeticmice, given oral benfotiamine or vehicle, were subjected to unilateral limb ischaemia. Reparative neovascularisation was analysed by histology. The expression of Nos3 and Casp3 was evaluated by real-time PCR, and the activation state of PKB/Akt was assessed by western blot analysis and immunohistochemistry. The functional importance of PKB/Akt in benfotiamine-induced effects was investigated using a dominant-negative construct. RESULTS:Diabetic muscles showed reduced transketolase activity, which was corrected by benfotiamine. Importantly, benfotiamine prevented ischaemia-induced toe necrosis, improved hindlimb perfusion and oxygenation, and restored endothelium-dependent vasodilation. Histological studies revealed the improvement of reparative neovascularisation and the inhibition of endothelial and skeletal muscle cell apoptosis. In addition, benfotiamine prevented the vascular accumulation of advanced glycation end products and the induction of pro-apoptotic caspase-3, while restoring proper expression of Nos3 and Akt in ischaemic muscles. The benefits of benfotiamine were nullified by dominant-negative PKB/Akt. In vitro, benfotiamine stimulated the proliferation of human EPCs, while inhibiting apoptosis induced by high glucose. In diabeticmice, the number of circulating EPCs was reduced, with the deficit being corrected by benfotiamine. CONCLUSIONS/ INTERPRETATION: We have demonstrated, for the first time, that benfotiamine aids the post-ischaemic healing of diabetic animals via PKB/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis. In addition, benfotiamine combats the diabetes-induced deficit in endothelial progenitor cells.
Authors: Robert J Lederman; Farrell O Mendelsohn; R David Anderson; Jorge F Saucedo; Alan N Tenaglia; James B Hermiller; William B Hillegass; Krishna Rocha-Singh; Thomas E Moon; M J Whitehouse; Brian H Annex Journal: Lancet Date: 2002-06-15 Impact factor: 79.321
Authors: Masuko Ushio-Fukai; Yan Tang; Tohru Fukai; Sergey I Dikalov; Yuxian Ma; Mitsuaki Fujimoto; Mark T Quinn; Patrick J Pagano; Chad Johnson; R Wayne Alexander Journal: Circ Res Date: 2002-12-13 Impact factor: 17.367
Authors: A M Schmidt; O Hori; J X Chen; J F Li; J Crandall; J Zhang; R Cao; S D Yan; J Brett; D Stern Journal: J Clin Invest Date: 1995-09 Impact factor: 14.808
Authors: Sanjay Rajagopalan; Emile R Mohler; Robert J Lederman; Farrell O Mendelsohn; Jorge F Saucedo; Corey K Goldman; John Blebea; Jennifer Macko; Paul D Kessler; Henrik S Rasmussen; Brian H Annex Journal: Circulation Date: 2003-09-22 Impact factor: 29.690
Authors: Lars P Kihm; Sandra Müller-Krebs; Julia Klein; Gregory Ehrlich; Laura Mertes; Marie-Luise Gross; Antonysunil Adaikalakoteswari; Paul J Thornalley; Hans-Peter Hammes; Peter P Nawroth; Martin Zeier; Vedat Schwenger Journal: J Am Soc Nephrol Date: 2011-04-21 Impact factor: 10.121
Authors: Cindy Jm Loomans; Rien van Haperen; Jacques M Duijs; Caroline Verseyden; Rini de Crom; Pieter Jm Leenen; Hemmo A Drexhage; Hetty C de Boer; Eelco Jp de Koning; Ton J Rabelink; Frank Jt Staal; Anton Jan van Zonneveld Journal: Mol Med Date: 2009-03-11 Impact factor: 6.354
Authors: G P Fadini; S Sartore; M Schiavon; M Albiero; I Baesso; A Cabrelle; C Agostini; A Avogaro Journal: Diabetologia Date: 2006-10-27 Impact factor: 10.122
Authors: Andrea Caporali; Elisabetta Pani; Anton J G Horrevoets; Nicolle Kraenkel; Atsuhiko Oikawa; Graciela B Sala-Newby; Marco Meloni; Brunella Cristofaro; Gallia Graiani; Aurelie S Leroyer; Chantal M Boulanger; Gaia Spinetti; Sung Ok Yoon; Paolo Madeddu; Costanza Emanueli Journal: Circ Res Date: 2008-06-19 Impact factor: 17.367