Vitamin B1 analog benfotiamine prevents diabetes-induced diastolic dysfunction and heart failure through Akt/Pim-1-mediated survival pathway.
BACKGROUND
The increasing incidence of diabetes mellitus will result in a new epidemic of heart failure unless novel treatments able to halt diabetic cardiomyopathy early in its course are introduced. This study aimed to determine whether the activity of the Akt/Pim-1 signaling pathway is altered at critical stages of diabetic cardiomyopathy and whether supplementation with vitamin B1 analog benfotiamine (BFT) helps to sustain the above prosurvival mechanism, thereby preserving cardiomyocyte viability and function.


RESULTS
Untreated streptozotocin-induced type 1 or leptin-receptor mutant type 2 diabetic mice showed diastolic dysfunction evolving to contractile impairment and cardiac dilatation and failure. BFT (70 mg/kg(-1)/d(-1)) improved diastolic and systolic function and prevented left ventricular end-diastolic pressure increase and chamber dilatation in both diabetic models. Moreover, BFT improved cardiac perfusion and reduced cardiomyocyte apoptosis and interstitial fibrosis. In hearts of untreated diabetic mice, the expression and activity of Akt/Pim-1 signaling declined along with O-N-acetylglucosamine modification of Akt, inhibition of pentose phosphate pathway, activation of oxidative stress, and accumulation of glycation end products. Furthermore, diabetes reduced pSTAT3 independently of Akt. BFT inhibited these effects of diabetes mellitus, thereby conferring cardiomyocytes with improved resistance to high glucose-induced damage. The phosphoinositide-3-kinase inhibitor LY294002 and dominant-negative Akt inhibited antiapoptotic action of BFT-induced and Pim-1 upregulation in high glucose-challenged cardiomyocytes.


CONCLUSIONS
These results show that BFT protects from diabetes mellitus-induced cardiac dysfunction through pleiotropic mechanisms, culminating in the activation of prosurvival signaling pathway. Thus, BFT merits attention for application in clinical practice.
Katare
Rajesh G
RG
Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, United Kingdom.
Caporali
Andrea
A
Oikawa
Atsuhiko
A
Meloni
Marco
M
Emanueli
Costanza
C
Madeddu
Paolo
P
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001783:Blood Flow Velocity; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003971:Diastole; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis / Q000517:prevention & control; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D007150:Immunohistochemistry; D051379:Mice; D008840:Microfilament Proteins; D009025:Morpholines / Q000494:pharmacology; D018384:Oxidative Stress; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013831:Thiamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D002867:Chromones; D008840:Microfilament Proteins; D009025:Morpholines; D051573:Proto-Oncogene Proteins c-pim-1; D050796:STAT3 Transcription Factor; D013831:Thiamine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C013835:benphothiamine; C527550:Ccdc88a protein, mouse; D033921:Vesicular Transport Proteins