Cerebral endothelial 3-mercaptopyruvate sulfurtransferase improves ischemia-induced cognitive impairment via interacting with protein phosphatase 2A.
10.1016/j.apsb.2024.11.015
- Author:
Li ZHU
1
;
Yi HUANG
2
;
Jing JIN
3
;
Rongjun ZOU
4
;
Rui ZUO
1
;
Yong LUO
1
;
Ziqing SONG
1
;
Linfeng DAI
1
;
Minyi ZHANG
1
;
Qiuhe CHEN
1
;
Yunting WANG
5
;
Wei WANG
1
;
Rongrong HE
6
;
Yang CHEN
1
Author Information
1. School of Pharmaceutics, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center, Guangzhou 510000, China.
2. Department of Stomatology, the First Affiliated Hospital, the School of Dental Medicine, Jinan University, Guangzhou 510632, China.
3. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100700, China.
4. The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510000, China.
5. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204-5037, USA.
6. Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou 510632, China.
- Publication Type:Journal Article
- Keywords:
3-Mercaptopyruvate sulfurtransferase;
Calpain2;
Cerebral endothelium;
Cognition;
Hydrogen sulfide;
Neuron;
Protein phosphatase 2A
- From:
Acta Pharmaceutica Sinica B
2025;15(1):314-330
- CountryChina
- Language:English
-
Abstract:
The catalytic activity of 3-mercaptopyruvate (3MP) sulfurtransferase (MPST) converts 3MP to hydrogen sulfide (H2S). However, the regulatory mechanisms governing MPST and its impact on the brain remain largely unexplored. Our study reveals the neuroprotective role of endothelial MPST-generated H2S, regulated by protein phosphatase 2A (PP2A). Bioinformatics analysis and RNA sequencing demonstrated that endothelial PP2A is associated with neurodegenerative disease pathways. Cerebral ischemic mice exhibited significant inactivation of endothelial PP2A, evidenced by the reduction of PP2Acα in the brain endothelium. Mice with endothelium-specific null PP2A (PP2AEC-cKO) exhibited neuronal loss, cognitive dysfunction, and long-term potentiation deficits. Postnatal inactivation of endothelial PP2A also contributes to cognitive dysfunction and neuronal loss. However, regaining endothelial PP2A activity by overexpressing Ppp2ca rescued neuronal dysfunction. Mechanistically, PP2A deficiency is intricately linked to the MPST-H2S signaling pathway. A robust reduction in endothelial MPST-dependent H2S production followed PP2A deficiency. Exogenous H2S treatment and AAV-mediated overexpression of MPST in brain endothelial cells significantly mitigated neuronal dysfunction in PP2AEC-cKO mice. Furthermore, PP2A deficiency promotes an increase in calcium influx and calpain2 phosphorylation, subsequently leading to MPST degradation. The PP2A activator (FTY720) and MPST activator (3MP sodium) both remarkably restored endothelial MPST-dependent H2S production, subsequently rescuing ischemia-induced neurological deficits. In conclusion, our study demonstrates that endothelial PP2A deficiency leads to MPST degradation by activating calpain2, thus damaging neuronal function.
