Reduced Cx43 Expression Induces Autophagy through Activation of the AMPK-mTOR-ULK1 Signaling Pathway in the Common Bile Duct Ligation Rat Heart

Xiaoyu Wang; Pingping Liao; He Dong; Aijie Liu; Qian Wang; Han Yang; Xiaolin Xu; Dongyue Chai; Lin Zhu; Lin Lyu

doi:10.1097/SHK.0000000000002360

Reduced Cx43 Expression Induces Autophagy through Activation of the AMPK-mTOR-ULK1 Signaling Pathway in the Common Bile Duct Ligation Rat Heart

Shock. 2024 Mar 13. doi: 10.1097/SHK.0000000000002360. Online ahead of print.

Authors

Xiaoyu Wang¹, Pingping Liao², He Dong, Aijie Liu¹, Qian Wang³, Han Yang⁴, Xiaolin Xu¹, Dongyue Chai¹, Lin Zhu¹, Lin Lyu

Affiliations

¹ Department of Anesthesiology, the Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong, China.
² Department of Geriatric Medicine, the Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong, China.
³ Department of Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong, China.
⁴ Department of Urology, the Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.

PMID: 38517263
DOI: 10.1097/SHK.0000000000002360

Abstract

Backgrounds: This study aimed to investigate the relationship between Cx43 expression and autophagy mediated by the AMPK-mTOR-Ulk1 signaling pathway in jaundice heart.

Methods: In this study, a jaundice model was established in common bile duct ligation (CBDL) rats. Cardiac injury was assessed using various methods including myocardial injury indicators, echocardiography, TEM, HE staining, Masson staining, IHC, and IF. We investigated the regulatory relationship between Cx43, autophagy, and the AMPK-mTOR-ULK pathway in vivo by administering autophagy agonists (Rapa), autophagy inhibitors (3-MA), and Cx43 inhibitors (Gap 26). In vitro, we observed the relationship between autophagy and the AMPK-mTOR-ULK1 pathway in cells by exposing them to the AMPK inhibitor Compound C and the AMPK activator AICAR.

Results: We found that CBDL induced autophagy through the AMPK-mTOR-ULK pathway, leading to the inhibition of myocardial dysfunction. Rapamycin pretreatment with CBDL3d exhibited a protective effect against myocardial injury and promoted autophagy. In contrast, 3-MA had no impact. Pretreatment with rapamycin at CBDL2w enhanced autophagy and aggravated cardiac injury; however, inhibition of autophagy using 3-MA attenuated cardiac injury. Cell viability was enhanced by AMPK inhibitors and inhibited by AMPK agonists. In addition, we observed that increased autophagy led to decreased Cx43 expression, which negatively affected cardiac function.

Conclusions: CBDL induces myocardial injury in rats and activates autophagy through the AMPK-mTOR-ULK pathway, resulting in decreased Cx43 protein levels. A moderate increase in early autophagy in CBDL can improve cardiac injury, while late inhibition of autophagy can reduce myocardial injury.