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Role of HSF1-upregulated AC6 in ameliorating heart failure in mice
Erlinda The1, Peizhao Du2, Yaowei Chang2
1Key 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.
Insights
Heat shock factor 1 (HSF1) alleviates heart failure by upregulating Adenylyl Cyclase 6 (AC6) and the cAMP/PKA pathway. This study clarifies the molecular mechanism by which HSF1 protects against pressure overload-induced cardiac dysfunction.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cellular Stress Response
Background:
- Heat shock factor 1 (HSF1) has shown potential in alleviating pressure overload-induced heart failure in mouse models.
- The precise molecular mechanisms underlying HSF1's cardioprotective effects remain incompletely understood.
- Adenylyl Cyclase 6 (AC6) is recognized for its role in ameliorating heart failure, but its connection to HSF1 is unexplored.
Purpose of the Study:
- To investigate whether HSF1 ameliorates heart failure by regulating Adenylyl Cyclase 6 (AC6).
- To elucidate the molecular mechanisms involved in HSF1-mediated regulation of AC6 in heart failure.
- To explore the association between HSF1 expression and AC6 levels in a pressure overload heart failure model.
Main Methods:
- A pressure overload-induced heart failure model was established in C57BL/6 mice using Transverse Aortic Constriction (TAC) for 4 weeks.
- Cardiac function and morphology were assessed using echocardiography and Masson staining.
- Expression levels of AC6 mRNA, HSF1, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP) were quantified using RT-QPCR, Western Blotting, and ELISA.
Main Results:
- TAC induced significant cardiac dysfunction, with increased expressions of AC6 mRNA, HSF1, PKA, and cAMP compared to the SHAM group.
- HSF1 knockout mice exhibited exacerbated cardiac dysfunction and reduced AC6, HSF1, PKA, and cAMP levels.
- HSF1 transgene mice demonstrated improved cardiac function and elevated AC6, HSF1, PKA, and cAMP levels compared to wild-type controls.
Conclusions:
- HSF1 plays a crucial role in ameliorating pressure overload-induced heart failure.
- HSF1 positively regulates the AC6/cAMP/PKA pathway, contributing to its cardioprotective effects.
- Targeting the HSF1-AC6 axis presents a potential therapeutic strategy for heart failure.
Purpose:
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.
Methods:
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.
Results:
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.
Conclusion:
In the pressure overload heart failure model, HSF1 can ameliorate heart failure by positively regulating the pathway of AC6/cAMP/PKA.
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