前列环素类似物调控TGFβ1- MKK3/6-p38MAPKα/β信号通路拮抗糖尿病心肌病的作用机制

The prevalence of diabetes has skyrocketed.There are about 35% patients with diabetic cardiomyopathy ,and the disease is highly dangerous.But, up to now, effective drugs for diabetic cardiomyopathy treatment is still absence. The p38 MAPK signaling pathway is activated by many stimulating factors, thus is a potential drug treatment target for anti myocardial hypertrophy. Our previous studies suggest that prostacyclin analogue beraprost sodium can inhibit the activity of the P38MAPK signaling pathway and slow the progression of diabetic cardiomyopathy. P38MAPK has 4 isoforms, among them, p38 alpha, p38 beta is most closely connected with myocardial. However, the current research on effect of p38 alpha and p38 beta in the pathogenic mechanism of diabetic cardiomyopathy is less,There are no studies to distinguish the role of the p38 alpha and p38 beta on diabetic cardiomyopathy. In addition, TGFβ1-MKK3/6-p38MAPKα/β signaling pathway play an important role in cardiac hypertrophy. Then, which subtype of the p38MAPK family will be the protective target for beraprost sodium? Or is the effect depends on the two isoforms competition? Can beraprost sodium through regulate the TGFβ1-MKK3/6-p38MAPKα/β signaling pathway to antagonize the diabetic myocardial hypertrophy？These are the urgent problems to be solved. Our study will elucidate the effect and mechanism of beraprost sodium in prevention and treatment of diabetic myocardial hypertrophy, also evaluate p38 alpha / beta as a new target for the treatment of diabetic cardiomyopathy. Our prospective results will be very helpful for the elucidation of beraprost sodium prevention of early diabetic cardiomyopathy and its mechanism.It has very important significance in clinical treatment for diabetic cardiomyopathy.

35%糖尿病患者存有糖尿病心肌病，糖尿病心肌病临床危害极大，但是临床上对于早期防治糖尿病心肌病缺乏有效的药物。p38MAPK信号通路在各种刺激引起的心肌肥厚反应中发挥作用，是一个潜在的抗心肌肥厚的药物治疗靶点，我们前期的研究结果提示前列环素类似物贝前列素钠通过抑制P38MAPK信号通路的活性，减缓糖尿病心肌病的进展。p38MAPK4种异构体中p38α、p38β和心肌关系最为密切，此外，TGFβ1- MKK3/6-p38MAPKα/β信号通路在心肌肥厚中发挥了重要作用。那么，贝前列素钠对心肌的保护作用靶点和哪个亚型有关？还是这两种亚型的竞争结果？贝前列素钠是否通过调控TGFβ1-MKK3/6-p38MAPKα/β信号通路来拮抗糖尿病的心肌肥厚？以上都是亟待解决的问题，本项目从多个角度探讨了贝前列素钠防治糖尿病心肌肥厚的作用，对于阐明贝前列素钠防治早期糖尿病心肌病的作用及其机制具有重要意义。

流行病学研究表明, 70%以上的糖尿病病人死于心血管疾病, 是非糖尿病人群心血管系统疾病死亡率的2 -3倍。预防心血管事件的发生是糖尿病治疗中非常重要的目标，其中, 糖尿病心肌病是糖尿病患者主要心脏并发症之一, 其发病率高, 危害极大, 直接导致了糖尿病病人心血管事件的高发生率和高病死率。心肌纤维化是糖尿病心肌病变的主要诱因，p38MAPK通路又是一个潜在的抗心肌纤维化的治疗靶点。我们前期的研究结果发现贝前列素钠的干预可以有效的减轻高糖毒性作用和炎症损伤。动物实验结果显示贝前列腺素钠可以通过抑制P38MAPK信号通路的活性，减轻炎症损伤，延缓心脏纤维化。为此，本研究深入探讨了贝前列素钠防治糖尿病心肌肥厚的作用效果及其机制；评估p38α/β作为糖尿病心肌病治疗新靶点的价值；并进一步探讨贝前列素钠调控TGFβ1-MKK3/6-p38MAPKα/β信号通路的机制。研究结果表明：1.通过干扰p38MAPK基因，抑制p38MAPK基因表达后，心肌成纤维细胞凋亡明显下降， QPCR结果分析，干扰组靶基因表达明显得到了抑制。2、过表达野生型P38α和P38β后，心肌细胞的生长变缓，凋亡比例增加；3、TGF-β1诱导后，心肌细胞的磷酸化P38蛋白表达量上升，P38α和P38β蛋白和RNA的表达量都上调，MKK3和MKK6的蛋白和RNA表达量下调；4、贝前列素钠干预后心肌成纤维细胞凋亡明显下降，可有效减轻TGF-β1诱导产生的心肌细胞损伤，可明确贝前列素钠作用通路确实在此；通过以上实验结果，本研究明确了p38MAPKα和p38MAPKβ 2个亚型在糖尿病心肌病发病中的作用机制。并进一步探清贝前列素钠可以拮抗心肌细胞纤维化，通过TGFβ1-MKK3/6-p38MAPKα/β信号通路的研究揭示了贝前列素纳抗心肌细胞增殖作用的机制。为治疗糖尿病心肌病提供新的思路和理论依据。