ZEB1-AS1 as a TRPML1 Inhibitor to Cause Lysosome Dysfunction and Cardiac Damage in Aged Mice

Engineering ›› 2024, Vol. 43 ›› Issue (12) : 183 -200. DOI: 10.1016/j.eng.2024.09.020

Research

Article

Heng Liu ^a^,^b^,^#
, Haiying Zhang ^c^,^#
, Han Lou ^a^,^d^,^e^,^#
, Jennifer Wang ^f
, Shengxin Hao ^a^,^d^,^e
, Hui Chen ^a^,^d^,^e
, Chen Chen ^a^,^d^,^e
, Lei Wang ^a^,^d^,^e
, Huimin Li ^a^,^d^,^e
, Ziyu Meng ^a^,^d^,^e
, Wenjie Zhao ^a^,^d^,^e
, Tong Zhao ^a^,^d^,^e
, Yuan Lin ^a^,^d^,^e
, Zhimin Du ^g^,^h^,ⁱ
, Xin Liu ^a^,^d^,^e^,^*
, Baofeng Yang ^d^,^e^,^*
, Yong Zhang ^a^,^d^,^e^,^*

Author information +

^aState Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China

^bPharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, China

^cEngineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, Haikou 571199, China

^dDepartment of Pharmacology (SKLFZCD, State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China

^eResearch Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China

^fDepartment of Medicine, Faculty of Medicine, Université de Laval, Quebec City, G1V 0A6, Canada

^gUniversity Key Laboratory of Drug Research, Heilongjiang Province, Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China

^hDepartment of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China

ⁱState Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau 999078, China

^* freyaliuxin@163.com (X. Liu),

^* yangbf@ems.hrbmu.edu.cn (B. Yang),

^* hmuzhangyong@hotmail.com (Y. Zhang).

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History +

Received	Accepted	Published
2024-04-17	2024-09-12	2024-12-01
Issue Date	Revised Date
2024-11-23	2024-09-05

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Abstract

The prevalence of cardiovascular diseases (CVDs) has increased markedly as the world population has aged. Long non-coding RNAs (lncRNAs) have been reported as novel regulators in diverse pathophysiological conditions. Here, we performed RNA sequencing (RNA-seq) and observed that the lncRNA Zeb1os1 (zinc finger E-box binding homeobox 1, opposite strand 1), which is known as ZEB1-AS1 (zinc finger E-box binding homeobox 1 antisense 1) in humans, was upregulated in the aged mice hearts, senescent cardiomyocytes, and human blood from elderly individuals. The human blood ZEB1-AS1 level was positively relevant to human age but negatively relevant to peak E to peak A (E/A). Silencing Zeb1os1 ameliorated diastolic dysfunction and cardiac senescence in aged mice. On the other hand, Zeb1os1 overexpression triggered cardiac dysfunction resembling that observed in aged mice. Mechanistically, we provide compelling evidence that Zeb1os1 interacts with the transient receptor potential mucolipin 1 (TRPML1) for ubiquitination (UB)-mediated degradation. This process inhibits lysosomal Ca²⁺ efflux, impairing lysosome function. In addition, the functional domain of Zeb1os1, which contains the key nucleotides responsible for the pro-senescence property of full-length Zeb1os1 in cardiomyocytes. Together, these data suggest that Zeb1os1 is a potential target for ameliorating lysosomal dysfunction and aging-related cardiac impairment.

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Keywords

Heart aging / Cardiomyocytes senescence / ZEB1-AS1 / TRPML1 / Lysosome

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Heng Liu, Haiying Zhang, Han Lou, Jennifer Wang, Shengxin Hao, Hui Chen, Chen Chen, Lei Wang, Huimin Li, Ziyu Meng, Wenjie Zhao, Tong Zhao, Yuan Lin, Zhimin Du, Xin Liu, Baofeng Yang, Yong Zhang. ZEB1-AS1 as a TRPML1 Inhibitor to Cause Lysosome Dysfunction and Cardiac Damage in Aged Mice. Engineering, 2024, 43(12): 183-200 DOI:10.1016/j.eng.2024.09.020