Benfotiamine improves functional recovery of the infarcted heart via activation of pro-survival G6PD/Akt signaling pathway and modulation of neurohormonal response.
Benfotiamine improves functional recovery of the infarcted heart via activation of pro-survival G6PD/Akt signaling pathway and modulation of neurohormonal response.
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DOI：
10.1016/j.yjmcc.2010.05.014
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发表时间：
2010-10
影响因子：
5
通讯作者：
Madeddu P
中科院分区：
文献类型：
--
作者：
Katare R;Caporali A;Emanueli C;Madeddu P
苯福硫胺(BFT)是一种转酮醇酶激活剂，可将葡萄糖导向磷酸戊糖途径。本研究调查了BFT是否能促进心肌梗死(MI)后的恢复，并探讨了其潜在的保护机制。非糖尿病和链脲佐菌素诱导的1型糖尿病小鼠给予BFT(70 mg/kg/d，饮水)，连续4周，然后进行心肌梗死或假手术。超声心动图监测心功能。心肌梗死后2周，用Millar尖端导管测量脑室内压，并采集心脏进行生化、免疫组织化学及表达分析。在假手术小鼠中未观察到治疗作用。糖尿病小鼠的心肌梗死后死亡率较高，血流动力学研究证实糖尿病对功能恢复的恶化影响。此外，糖尿病小鼠心肌细胞凋亡增加，修复性血管生成减少，瘢痕更大，氧化应激增强，促进生存的血管内皮生长因子受体-2/Akt/Pim-1信号通路被钝化激活。BFT可改善糖尿病和非糖尿病小鼠的心肌梗死后存活、功能恢复和新生血管，并减少心肌细胞凋亡和神经激素激活。此外，BFT还刺激了磷酸戊糖途径酶的活性，导致氧化应激减轻，VEGF受体-2和Akt的磷酸化/激活，Pim-1，pBad和Bcl2水平升高。在抑制磷酸戊糖途径的关键酶葡萄糖-6-磷酸脱氢酶或抑制Akt方面进行了对比。BFT通过刺激有利于生存的机制和抑制神经激素反应，有利于心肌梗塞后的恢复。这些结果可能对心肌缺血的治疗有一定的指导意义。
Benfotiamine (BFT) is a transketolase activator that directs glucose to the pentose phosphate pathway. The present study investigated whether BFT improves the recovery after myocardial infarction (MI) and explored underlying mechanisms of protection. Non-diabetic and streptozotocin-induced type 1 diabetic mice were supplemented with BFT (70 mg/kg/day in drinking water) for 4 weeks and then subjected to MI or sham operation. Cardiac function was monitored by echocardiography. At two weeks post-MI, intra-ventricular pressure was measured by Millar tip-catheter and hearts were collected for biochemical, immunohistochemical and expressional analyses. No treatment effect was observed in sham-operated mice. Post-MI mortality was higher in diabetic mice and hemodynamic studies confirmed the worsening effect of diabetes on functional recovery. Furthermore, diabetic mice demonstrated increased cardiomyocyte apoptosis, reduced reparative angiogenesis, larger scars, enhanced oxidative stress, and blunted activation of the pro-survival VEGF receptor-2/Akt/Pim-1 signaling pathway. BFT improved post-MI survival, functional recovery and neovascularization and reduced cardiomyocyte apoptosis and neurohormonal activation in diabetic as well as in non-diabetic mice. In addition, BFT stimulated the activity of pentose phosphate pathway enzymes, leading to reduction of oxidative stress, phosphorylation/activation of VEGF receptor-2 and Akt and increased Pim-1, pBad and Bcl-2 levels. These effects were contrasted on silencing glucose-6-phosphate dehydrogenase, the key enzyme in pentose phosphate pathway, or inhibiting Akt. BFT benefits post-MI recovery through stimulation of pro-survival mechanisms and containment of neurohormonal response. These results may have implications for the treatment of myocardial ischemia.
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DOI：
10.1161/circheartfailure.109.903450
发表时间：
2010-03
期刊：
Circulation. Heart failure
影响因子：
--
作者：
Katare RG;Caporali A;Oikawa A;Meloni M;Emanueli C;Madeddu P
通讯作者：
Madeddu P
DOI：
10.1016/0735-1097(93)90348-5
发表时间：
1993-03-15
影响因子：
24
作者：
GRANGER, CB;CALIFF, RM;TOPOL, EJ
通讯作者：
TOPOL, EJ
影响因子：
7.7
作者：
Babaei-Jadidi, R;Karachalias, N;Thornalley, PJ
通讯作者：
Thornalley, PJ
影响因子：
4.8
作者：
Moe, GW;Rouleau, JL;Packer, M
通讯作者：
Packer, M
影响因子：
2.8
作者：
Chatterjee, K
通讯作者：
Chatterjee, K