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Diabetologia
Published in: Diabetologia 2/2006

01-02-2006 | Article

Benfotiamine accelerates the healing of ischaemic diabetic limbs in mice through protein kinase B/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis

Authors: S. Gadau, C. Emanueli, S. Van Linthout, G. Graiani, M. Todaro, M. Meloni, I. Campesi, G. Invernici, F. Spillmann, K. Ward, P. Madeddu

Published in: Diabetologia | Issue 2/2006

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Abstract

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.
Literature
1.
2.
Hiatt WR (2001) Medical treatment of peripheral arterial disease and claudication. N Engl J Med 344:1608–1621PubMedCrossRef
3.
Currie CJ, Morgan CL, Peters JR (1998) The epidemiology and cost of inpatient care for peripheral vascular disease, infection, neuropathy, and ulceration in diabetes. Diabetes Care 21:42–48PubMedCrossRef
4.
Humphrey LL, Palumbo PJ, Butters MA et al (1994) The contribution of non-insulin-dependent diabetes to lower-extremity amputation in the community. Arch Intern Med 154:885–892PubMedCrossRef
5.
Regensteiner JG, Hiatt WR (2002) Current medical therapies for patients with peripheral arterial disease: a critical review. Am J Med 112:4957PubMedCrossRef
6.
Rivard A, Silver M, Chen D et al (1999) Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am J Pathol 154:355–363PubMed
7.
Taniyama Y, Morishita R, Hiraoka K et al (2001) Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model: molecular mechanisms of delayed angiogenesis in diabetes. Circulation 104:2344–2350PubMedCrossRef
8.
Emanueli C, Graiani G, Salis MB, Gadau S, Desortes E, Madeddu P (2004) Prophylactic gene therapy with human tissue kallikrein ameliorates limb ischemia recovery in type 1 diabetic mice. Diabetes 53:1096–1103PubMedCrossRef
9.
Lederman RJ, Mendelsohn FO, Anderson RD et al (2002) Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 359:2053–2058PubMedCrossRef
10.
Rajagopalan S, Mohler ER 3rd, Lederman RJ et al (2003) Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation 108:1933–1938PubMedCrossRef
11.
12.
The DCCT Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986CrossRef
13.
UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853CrossRef
14.
Wei M, Gaskill SP, Haffner SM, Stern MP (1998) Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality. The San Antonio Heart Study. Diabetes Care 21:1167–1172PubMedCrossRef
15.
Ushio-Fukai M, Tang Y, Fukai T et al (2002) Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis. Circ Res 91:1160–1167PubMedCrossRef
16.
Tojo T, Ushio-Fukai M, Yamaoka M, Ikeda S, Patrshev N, Alexander W (2005) Role of gp91phox (Nox2)-containing NAD(P)H oxidase in angiogenesis in response to hindlimb ischemia. Circulation 111:2347–2355PubMedCrossRef
17.
Griendling KK, Sorescu D, Ushio-Fukai M (2000) NAD(P)H oxidase. Role in cardiovascular biology and disease. Circ Res 86:494–501PubMed
18.
Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820PubMedCrossRef
19.
McClain DA, Paterson AJ, Roos MD, Wei X, Kudlow JE (1992) Glucose and glucosamine regulate growth factor gene expression in vascular smooth muscle cells. Proc Natl Acad Sci U S A 89:8150–8154PubMedCrossRef
20.
Giardino I, Edelstein D, Brownlee M (1994) Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity. A model for intracellular glycosylation in diabetes. J Clin Invest 94:110–117PubMed
21.
Schmidt AM, Hori O, Chen JX et al (1995) Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest 96:1395–1403PubMedCrossRef
22.
Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M (2001) Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 108:1341–1348PubMedCrossRef
23.
Cai S, Khoo J, Channon KM (2005) Augmented BH4 by gene transfer restores nitric oxide synthase function in hyperglycemic human endothelial cells. Cardiovasc Res 65:823–831PubMedCrossRef
24.
Gerber HP, McMurtrey A, Kowalski J et al (1998) Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 273:30336–30343PubMedCrossRef
25.
Dimmeler S, Fisslthaler B, Fleming I, Hermann C, Busse R, Zeiher AM (1999) Activation of nitric oxide synthase in endothelial cells via Akt-dependent phosphorylation. Nature 399:601–605PubMedCrossRef
26.
Kim I, Kim HG, So J-N et al (2000) Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. Circ Res 86:24–29PubMed
27.
Krankel N, Adams V, Linke A et al (2005) Hyperglycemia reduces survival and impairs function of circulating blood-derived progenitor cells. Arterioscler Thromb Vasc Biol 25:698–703PubMedCrossRef
28.
Dimmeler S, Aiche A, Vasa M et al (2001) HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI3-kinase/Akt pathway. J Clin Invest 108:391–397PubMedCrossRef
29.
Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ (2003) Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 52:2110–2120PubMedCrossRef
30.
Hammes HP, Du X, Edelstein D et al (2003) Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 9:294–299PubMedCrossRef
31.
Shindo H, Okamoto K, Totsu J (1967) Transport of organic compounds through biological membranes. I. Accumulative uptake of S-benzoylthiamine by human erythrocytes. Chem Pharm Bull (Tokyo) 15:295–302
32.
Ziems M, Netzel M, Bitsch I (2000) Biokinetic parameters and metabolism of S-benzoylthiamine-O-monophosphate. Biofactors 11:109–110PubMed
33.
Emanueli C, Maestri R, Corradi D et al (1999) Dilated and failing cardiomyopathy in bradykinin B2 receptor knockout mice. Circulation 100:2359–2365PubMed
34.
Emanueli C, Minasi A, Zacheo A et al (2001) Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia. Circulation 103:125–132PubMed
35.
Condorelli G, Drusco A, Stassi et al (2002) Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci U S A 99:12333–12338PubMedCrossRef
36.
Horiuchi S, Araki N, Morino Y (1991) Immunochemical approach to characterize advanced glycation end products of the Maillard reaction: evidence for the presence of a common structure. J Biol Chem 266:7329–7332PubMed
37.
Kaji Y, Usui T, Oshika T et al (2000) Advanced glycation end products in diabetic corneas. Invest Ophthalmol Vis Sci 41:362–368PubMed
38.
Chamberlain BR, Buttery JE, Pannall PR (1996) A stable reagent mixture for the whole blood transketolase assay. Ann Clin Biochem 33:352–354PubMed
39.
Emanueli C, Salis MB, Van Linthout S et al (2004) Akt/protein kinase B and endothelial nitric oxide synthase mediate muscular neovascularization induced by tissue kallikrein gene transfer. Circulation 110:1638–1644PubMedCrossRef
40.
Tepper OM, Galiano RD, Capla JM et al (2002) Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106:2781–2786PubMedCrossRef
41.
Loomans CJ, de Koning EJ, Staal FJ et al (2004) Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes 53:195–199PubMedCrossRef
42.
Saito N, Kimura M, Kuchiba A, Itokawa Y (1987) Blood thiamine levels in outpatients with diabetes mellitus. J Nutr Sci Vitaminol 33:421–430PubMed
43.
Havivi E, Bar On H, Reshef A, Raz I (1991) Vitamins and trace metals status in non-insulin dependent diabetes mellitus. Int J Vitam Nutr Res Res 61:328–333PubMed
44.
Valerio G, Franzese A, Poggi V, Patrini C, Laforenza U, Tenore A (1999) Lipophilic thiamine treatment in longstanding insulin-dependent diabetes mellitus. Acta Diabetol 36:73–76PubMedCrossRef
45.
Ishii H, Jirousek MR, Koya D et al (1996) Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 272:728–731PubMedCrossRef
46.
Hammes HP, Martin S, Federlin K, Geisen K, Brownlee M (1991) Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy. Proc Natl Acad Sci U S A 88:11555–11558PubMedCrossRef
47.
Waltenberger J, Lange J, Kranz A (2000) Vascular endothelial growth factor-A-induced chemotaxis of monocytes is attenuated in patients with diabetes mellitus: A potential predictor for the individual capacity to develop collaterals. Circulation 102:185–190PubMed
48.
Lukienko PI, Mel’nichenko NG, Zverninskii IV, Zabrodskaya SV (2000) Antioxidant properties of thiamine. Bull Exp Biol Med 130:874–876PubMed
49.
Hayashi CM, Nagai R, Miyazaki K et al (2002) Conversion of Amadori products of the Maillard reaction to N-epsilon-(carboxymethyl) lysine by short-term heating: possible detection of artifacts by immunohistochemistry. Lab Invest 82:795–807
50.
Brunet A, Bonni A, Zigmond MJ et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868PubMedCrossRef
51.
Ohashi H, Takagi H, Oh H et al (2004) Phosphatidylinositol 3-kinase/Akt regulates angiotensin II-induced inhibition of apoptosis in microvascular endothelial cells by governing survivin expression and suppression of caspase-3 activity. Circ Res 94:785–793PubMedCrossRef
52.
Skurk C, Maatz H, Kim HS et al (2004) The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP. J Biol Chem 279:1513–1525PubMedCrossRef
Metadata
Title
Benfotiamine accelerates the healing of ischaemic diabetic limbs in mice through protein kinase B/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis
Authors
S. Gadau
C. Emanueli
S. Van Linthout
G. Graiani
M. Todaro
M. Meloni
I. Campesi
G. Invernici
F. Spillmann
K. Ward
P. Madeddu
Publication date
01-02-2006
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 2/2006
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-005-0103-5

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