Role of the HSF1/AMPK signaling pathway in the pathogenesis of ferroptosis-involving diabetic cardiomyopathy

Zhou Kang, Song Junhua, Zhou Mi, Yang Yanli, Chen Haibin, Zhang Li

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Journal of Chongqing Medical University ›› 2024, Vol. 49 ›› Issue (10) : 1074-1080. DOI: 10.13406/j.cnki.cyxb.003607
Basic research

Role of the HSF1/AMPK signaling pathway in the pathogenesis of ferroptosis-involving diabetic cardiomyopathy

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Abstract

Objective To investigate the effect of ferroptosis regulated by the heat shock factor 1（HSF1）/adenosine 5’-monophosphate-activated protein kinase（AMPK） signaling pathway on the pathogenesis of diabetic cardiomyopathy（DCM）. Methods This was an experimental study with a blank control and multiple experimental controls. H9c2 cells were randomly divided into 4 groups：low glucose group（control，Con），high glucose（HG） group，HG+HSF1 group，and HG+HSF1+compound C（CC） group. The cells were stained by rhodamine colloid protein，and tested for mitochondrial reactive oxygen species（ROS） and cellular lipid ROS. The AMPK signal expression was analyzed by Western blot. Male C57/BL6 mice were randomly divided into four groups： negative control（NC） group，NC+HSF1 group，DM group，and DM+HSF1 group，with 12 mice in each group. The cardiovascular function parameters of mice were evaluated by echocardiography. Results Compared with the Con group，the levels of HSF1 and pAMPK/AMPK in the HG group decreased significantly（P=0.005，0.002），and the relative cell surface area，mitochondrial Fe2+ level，mitochondrial ROS level，and cellular lipid ROS level increased significantly（P=0.001，0.003，0.006，0.002）. Compared with the HG group，the HG+HSF1 group significantly reversed these changes（P=0.001，0.001，0.002，0.006，0.007，0.003），but the reversal effect of HSF1 was obviously weakened when CC was added（P<0.05）. Compared with the NC group，the ejection fraction，fractional shortening，mitral ratio of peak early to late diastolic filling velocity（E/A），and E'/A' as well as the expression levels of HSF1 and pAMPK/AMPK in heart tissues in the DM group were significantly decreased（P<0.01），and the levels of Fe2+，ROS，malondialdehyde，and 4-hydroxynonenal protein in heart tissues were significantly increased（P=0.004，0.003，0.001，0.004）；the DM+HSF1 group significantly reversed these changes. Conclusion HSF1 plays a cardioprotective role in the pathological process of DCM，and its anti-ferroptosis effect may be related to AMPK-dependent lipid metabolism and mitochondrial homeostasis regulation.

Key words

heat shock factor 1 / adenosine 5’-monophosphate-activated protein kinase / diabetic cardiomyopathy / mouse / ferroptosis

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Zhou Kang , Song Junhua , Zhou Mi , et al . Role of the HSF1/AMPK signaling pathway in the pathogenesis of ferroptosis-involving diabetic cardiomyopathy. Journal of Chongqing Medical University. 2024, 49(10): 1074-1080 https://doi.org/10.13406/j.cnki.cyxb.003607

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