PTP1B Inhibition Improves Mitochondrial Dynamics to Alleviate Calcific Aortic Valve Disease Via Regulating OPA1 Homeostasis

• Published in: JACC. Basic to translational science 2022-07, Vol.7 (7), p.697-712
• Main Authors: Liu, Feng, Chen, Jinyong, Hu, Wangxing, Gao, Chenyang, Zeng, Zhiru, Cheng, Si, Yu, Kaixiang, Qian, Yi, Xu, Dilin, Zhu, Gangjie, Zhao, Jing, Liu, Xianbao, Wang, Jian'an
• Format: Article
• Language: English
• Subjects: calcific aortic valve disease; mitochondrial biogenesis; optic atrophy 1; Original Research - Preclinical; protein tyrosine phosphatase 1B; valvular interstitial cells
• ISSN: 2452-302X; 2452-302X
• DOI: 10.1016/j.jacbts.2022.03.002

[Display omitted] •Increased PTP1B was observed in the human calcified aortic valve leaflets and VIC osteogenesis, which indicated a novel association of PTP1B with aortic valve calcification.•MSI-1436, a specific pharmacological PTP1B inhibitor, attenuated osteogenic and myofibrogenic differentiation of VICs, which coincided with preventing aortic valve fibrocalcific disease in a diet-induced mouse model of CAVD.•Treatment of CAVD with PTP1B inhibitor mitigated the disorder of aortic jet velocity and mean gradient in vivo.•PTP1B inhibition preserved the mitochondrial biogenesis and function in VIC osteogenesis via regulating OPA1 homeostasis. There are currently no pharmacological therapies for calcific aortic valve disease (CAVD). Here, we evaluated the role of protein tyrosine phosphatase 1B (PTP1B) inhibition in CAVD. Up-regulation of PTP1B was critically involved in calcified human aortic valve, and PTP1B inhibition had beneficial effects in preventing fibrocalcific response in valvular interstitial cells and LDLR−/− mice. In addition, we reported a novel function of PTP1B in regulating mitochondrial homeostasis by interacting with the OPA1 isoform transition in valvular interstitial cell osteogenesis. Thus, these findings have identified PTP1B as a potential target for preventing aortic valve calcification in patients with CAVD.