The Erlinda, Du Peizhao, Chang Yaowei, Dai Fangjie, Wei Chunyan, Li Jiming
Key Laboratory of Arrhythmias of the Ministry of Education of China, and Department of Cardiovascular Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
Department of Cardiovascular Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
Environ Toxicol Pharmacol. 2016 Oct;47:79-85. doi: 10.1016/j.etap.2016.08.015. Epub 2016 Aug 22.
Our previous studies discovered that Heat shock factor 1(HSF1) can alleviate pressure overload induced heart failure in mice. However, its molecular mechanisms are yet to be further explained. Many studies have already verified that Adenylyl Cyclase 6 (AC6) can ameliorate heart failure, but it is still unknown whether or not the pathway HSF1 is involved in the process. Our preliminary experiment showed that the expression level of AC6 is positively associated with HSF1. Therefore, in the present study, we aimed to explore whether HSF1 can play its role in ameliorating heart failure by regulating AC6, and how the potential internal mechanisms work.
We applied the Transverse Aortic Constriction (TAC) for 4 weeks to develop the C57BL/6 mice pressure overload induced heart failure model. First, the mice were divided into TAC group and SHAM group. Changes in the cardiac function and morphology of the mice were observed by an ultrasonic device and Masson staining slices, expressions of AC6 mRNA were observed by RT-QPCR, expressions of HSF1 and proteinkinase A (PKA) were examined by Western Blotting, and the levels of cyclic adenosine monophosphate (cAMP) from aortic blood were measured by ELISA. Second, the TAC group were further divided into subgroups of HSF1 transgene mice, HSF1 knockout mice and wild type mice, followed by the aforesaid observations.
In the SHAM group, no obvious variations of cardiac function, AC6 mRNAHSF1, PKA, cAMP and other test results were found among each of the subgroups. Compared to the SHAM group, the TAC group presented clearly weakened heart functions, while, expressions of AC6 mRNA, HSF1, PKA and cAMP all recorded obvious increases. In the TAC group, compared to the WT subgroup, the HSF1 KO subgroup presented decreases in expressions of AC6 mRNA, HSF1, PKA and cAMP, and at the same time, the heart functions were weaker, while, the HSF1 TG subgroup recorded the contrary results.
In the pressure overload heart failure model, HSF1 can ameliorate heart failure by positively regulating the pathway of AC6/cAMP/PKA.
我们之前的研究发现热休克因子1（HSF1）可减轻小鼠压力超负荷诱导的心力衰竭。然而，其分子机制尚待进一步阐明。许多研究已证实腺苷酸环化酶6（AC6）可改善心力衰竭，但HSF1是否参与该过程仍不清楚。我们的初步实验表明AC6的表达水平与HSF1呈正相关。因此，在本研究中，我们旨在探讨HSF1是否可通过调节AC6在改善心力衰竭中发挥作用，以及潜在的内在机制是如何起作用的。
我们应用横向主动脉缩窄（TAC）4周来建立C57BL/6小鼠压力超负荷诱导的心力衰竭模型。首先，将小鼠分为TAC组和假手术组。通过超声装置和Masson染色切片观察小鼠的心功能和形态变化，通过RT-QPCR观察AC6 mRNA的表达，通过蛋白质印迹法检测HSF1和蛋白激酶A（PKA）的表达，并通过ELISA测定主动脉血中环磷酸腺苷（cAMP）的水平。其次，将TAC组进一步分为HSF1转基因小鼠亚组、HSF1基因敲除小鼠亚组和野生型小鼠亚组，随后进行上述观察。
在假手术组中，各亚组的心功能、AC6 mRNA、HSF1、PKA、cAMP等检测结果均无明显变化。与假手术组相比，TAC组的心功能明显减弱，而AC6 mRNA、HSF1、PKA和cAMP的表达均明显增加。在TAC组中，与野生型亚组相比，HSF1基因敲除亚组的AC6 mRNA、HSF1、PKA和cAMP表达降低，同时心功能较弱，而HSF1转基因亚组则得到相反的结果。
在压力超负荷心力衰竭模型中，HSF1可通过正向调节AC6/cAMP/PKA途径改善心力衰竭。
