Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice

Mingyuan Wang; Jiang Zou; Jinjin Wang; Meidong Liu; Ke Liu; Nian Wang; Kangkai Wang

doi:10.1016/j.omtn.2022.07.009

Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice

Mol Ther Nucleic Acids. 2022 Jul 11:29:312-328. doi: 10.1016/j.omtn.2022.07.009. eCollection 2022 Sep 13.

Authors

Mingyuan Wang^{1

2

3

4}, Jiang Zou¹, Jinjin Wang⁴, Meidong Liu¹, Ke Liu¹, Nian Wang¹, Kangkai Wang¹

Affiliations

¹ Department of Pathophysiology, Key Laboratory of Sepsis Translational Medicine of Hunan, School of Basic Medical Science, Central South University, 410008 Changsha, Hunan, China.
² National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008 Changsha, Hunan, China.
³ Department of Geratic Surgery, Xiangya Hospital, Central South University, 410008 Changsha, Hunan, China.
⁴ Department of Gynaecology, the Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, 412000 Zhuzhou, Hunan, China.

Abstract

Myocardial infarction (MI) is a cardiovascular disease with high morbidity and mortality. Clinically, rehabilitation after massive MI often has a poor prognosis. Therefore, it is necessary to explore the therapeutic methods of myocardial protection after MI. As a first-line treatment for type 2 diabetes, metformin has been found to have a certain protective effect on myocardial tissue. However, its pharmacological mechanism remains unclear. In this study, we investigated key factors that reduced MI with metformin. Through in vivo, in vitro, and in silico analyses, we identified HSF1 as a key target for metformin. HSF1 could up-regulate the transcriptional level of AMPKα2 through transcriptional activation and stimulate the activity of the downstream AMPK/mTOR signaling pathway. Metformin stimulated cardiomyocytes to form stress granules (SGs), and knockdown of HSF1 reversed this process. Furthermore, HSF1 exhibited better in vitro affinity for metformin than AMPK, suggesting that HSF1 may be a more sensitive target for metformin.

Keywords: AMPK; HSF1; metformin; myocardial infarction (MI); stress granules.