Vitamin B1 analog benfotiamine prevents diabetes-induced diastolic dysfunction and heart failure through Akt/Pim-1-mediated survival pathway.
Vitamin B1 analog benfotiamine prevents diabetes-induced diastolic dysfunction and heart failure through Akt/Pim-1-mediated survival pathway.
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DOI：
10.1161/circheartfailure.109.903450
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发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
Madeddu P
中科院分区：
文献类型：
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作者：
Katare RG;Caporali A;Oikawa A;Meloni M;Emanueli C;Madeddu P
糖尿病发病率的增加将导致新的心力衰竭流行，除非引入能够在病程早期阻止糖尿病心肌病的新的治疗方法。本研究旨在确定Akt/Pim-1信号通路的活性是否在糖尿病心肌病变的关键阶段发生改变，以及补充维生素B1类似物苯福硫胺(BFT)是否有助于维持上述存活机制，从而保护心肌细胞的活力和功能。未经治疗的链脲佐菌素诱导的1型或瘦素受体突变的2型糖尿病小鼠表现出舒张期功能障碍，演变为收缩功能障碍和心脏扩张和衰竭。BFT(70 mg/kg−1/d−1)可改善两种糖尿病模型的舒缩功能，防止左室舒张末压升高和内腔扩张。此外，BFT可改善心脏灌注量，减少心肌细胞凋亡和间质纤维化。在未经治疗的糖尿病小鼠心脏中，Akt/Pim-1信号通路的表达和活性随着Akt的O-N-乙酰氨基葡萄糖修饰、戊糖磷酸途径的抑制、氧化应激的激活和糖基化终产物的积累而下降。此外，糖尿病使信号转导和转录激活子3的磷酸化水平降低，而不依赖Akt。BFT可抑制糖尿病的这些影响，从而使心肌细胞对高糖诱导的损伤具有更好的抵抗力。磷脂酰肌醇-3-激酶抑制剂LY294002和显性负性Akt可抑制BFT和Pim-1上调对高糖刺激的心肌细胞的抗凋亡作用。这些结果表明，BFT通过多效性机制保护糖尿病所致的心功能不全，最终激活生存信号通路。因此，BFT在临床应用中值得重视。
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. 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 signal transducer and activator of transcription 3 phosphorylation 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 and Pim-1 upregulation in high glucose-challenged cardiomyocytes. 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.