Low-Intensity Pulsed Ultrasound Counteracts Advanced Glycation End Products-Induced Corpus Cavernosal Endothelial Cell Dysfunction via Activating Mitophagy

Yuzhuo Chen; Ming Xiao; Liangyu Zhao; Yongquan Huang; Yuhong Lin; Ting Xie; Jiali Tian; Qi Wang; Yuxin Tang; Zhongzhen Su

doi:10.3390/ijms232314887

Low-Intensity Pulsed Ultrasound Counteracts Advanced Glycation End Products-Induced Corpus Cavernosal Endothelial Cell Dysfunction via Activating Mitophagy

Int J Mol Sci. 2022 Nov 28;23(23):14887. doi: 10.3390/ijms232314887.

Authors

Yuzhuo Chen^{1

2}, Ming Xiao^{2

3}, Liangyu Zhao³, Yongquan Huang¹, Yuhong Lin¹, Ting Xie¹, Jiali Tian¹, Qi Wang¹, Yuxin Tang³, Zhongzhen Su¹

Affiliations

¹ Department of Ultrasound, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
² Guangdong Provincial Key Laboratory of Biomedical Imaging, Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
³ Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.

Abstract

Injury to corpus cavernosal endothelial cells (CCECs) is an important pathological basis of diabetes mellitus-induced erectile dysfunction (DMED), while low-intensity pulsed ultrasound (LIPUS) has been shown to improve erectile function in DMED. To further understand its therapeutic mechanism of action, in this study, we first demonstrated increased apoptosis and shedding in the CCECs of DMED patients, accompanied by significant mitochondrial injury by immunohistochemistry and electron microscopy of corpus cavernosum tissue. Next, we used advanced glycation end products (AGEs) to simulate the diabetic environment in vitro and found that AGES damaged mitochondria and inhibited angiogenesis in CCECs in a dose-dependent manner, while LIPUS treatment significantly reversed its effects. Mechanistic studies based on transcriptome sequencing showed that LIPUS significantly up-regulated LC3 and PARKIN protein levels in mitochondria, promoted mitophagy, and affected mitochondrial dynamics and reactive oxygen species (ROS) production. In addition, the protective effects of LIPUS were abrogated when mitophagy was inhibited by 3-methyladenine. In summary, LIPUS exerted potent inhibitory effects on AGES-induced CCEC failure via mitophagy, providing a theoretical basis for DMED treatment that encompasses the protection of endothelial structure and function.

Keywords: angiogenesis; corpus cavernosal endothelial cells (CCECs); diabetes mellitus-induced erectile dysfunction (DMED); low-intensity pulsed ultrasound (LIPUS); mitophagy; regenerative medicine.

MeSH terms

Animals
Endothelial Cells*
Glycation End Products, Advanced
Humans
Male
Mitophagy*
Rats
Rats, Sprague-Dawley
Ultrasonic Waves

Substances

Glycation End Products, Advanced

Grants and funding

This work was support by grants from China Postdoctoral Science Foundation (2021M703747, L.Z.); Guangdong Basic and Applied Basic Research Foundation (2021A1515111109, L.Z.); National Natural Science Foundation of China (82201756, Z.L.; and 82071636, Y.T.); the open funds of Guangdong Provincial Key Lab of Biomedical Imaging (GPKLBI202104, L.Z.); Zhuhai social development field science and technology plan project (2220004000310, Y.L.); the Guangdong Basic and Applied Basic Research Fund Regional Joint Fund—Youth Fund Project (2019A1515110457, Y.H.); Core talent fund of the Fifth Afliated Hospital of Sun Yat-sen University (310103050302-220904094228, Z.S.).