热休克转录因子1在小鼠心脏淀粉样变疾病中的作用机制研究

The role of HSF1 in cardiac amyloidosis in mice

目的:探讨热休克转录因子1(HSF1)在心脏淀粉样变疾病中的作用机制。方法:将30只HSF1敲除小鼠随机分为3个实验组,HSF1敲除型空白对照组、敲除型淀粉样变模型组及替普瑞酮治疗组;将20只野生型小鼠随机分为2个实验组,野生型空白对照组、野生型淀粉样变模型组,每组均为10只。进行淀粉样变诱导实验构建淀粉样变疾病模型。模型构建2个月后处死小鼠,通过刚果红染色、免疫组织化学染色、分子生物学检测,比较各个实验组心脏组织中热休克蛋白及淀粉样变沉积情况,以及肝脏、脾脏、胃、肠舌、皮肤组织中的淀粉样变沉积情况。结果:淀粉样变诱导实验后,野生型小鼠心脏组织中热休克蛋白70(HSP70)mRNA的表达水平较空白组显著升高(P<0.05),HSF1敲除小鼠淀粉样变疾病模型的心脏组织中HSP70mRNA的表达水平显著低于野生型实验组(P<0.05),且心脏淀粉样变沉积程度显著高于野生型实验组。给予HSP70诱导剂替普瑞酮后,敲除型实验组心脏组织中的HSP70mRNA的表达水平明显升高,其淀粉样沉积程度明显得到改善。而未进行淀粉样变诱导实验的空白组,不管是野生型小鼠还是敲除型小鼠均未见淀粉样物质沉积。此外,敲除型实验组小鼠血清中心肌肌钙蛋白T(TnT)表达显著高于野生型实验组,而给予替普瑞酮治疗后表达下降。结论:HSF1可能通过对HSP70的调控影响心脏淀粉样变的沉积情况,该结果为心脏淀粉样变的防治提供了新的思路。

Objective：To probe the role of heat shock factor 1（HSF1）in cardiac amyloidosis in mice model. Methods：Thirty female HSF1-/-mice were divided into 3 random groups（negative control of HSF1-/-,AA induction of HSF1-/-,AA induction of HSF1-/-with GGA）and 20 wide type mice were divided into 2 random groups（negative control of HSF1＋/＋,AA induction of HSF1＋/＋）.The expressions of HSP70 mRNA in heart were detected by Real-Time PCR and Western Blot;amyloid degrees were assessed by Congo Red and immunohischemistry methods in the heart,liver,spleen,stomach,intestine,tongue,skin. Results：After amyloid induction,the expression of HSP70 mRNA was increased in wide type mouse,and the expression of HSP70 mRNA was markedly downregulated upon loss of HSF1 in the heart;HSP70 expression was suppressed by the loss of HSF1 even with exogenous amyloid application;HSF1 deficiency promotes cardiac AApoAⅡ deposition.However,treated with GGA,the expression of HSP70 mRNA obviously increased in the heart,and the cardiac amyloid deposition was mitigated in HSF1-/-mice.While there was no any amyloid deposition observed in HSF1-/-and wide type mice without amyloid induction.In addition,the serum levels of Troponin T protein were higher in HSF1-/-than in wild-type mice,while reduced after treated with GGA in HSF1-/-mice. Conclusions：The loss of HSF1 induced a dysregulation of proteostasis in the heart via an inhibition of the HSP70,leading to the accumulation of amyloid fibrils in heart tissue.It demonstrated that agents that induce HSF1 activation can serve as potential therapeutics in the treatment of cardiac amyloidosis.