2. Academic Validation
  3. Cysteine and glycine rich protein 2 exacerbates vascular fibrosis in pulmonary hypertension through the nuclear translocation of yes-associated protein and transcriptional coactivator with PDZ-binding motif

Cysteine and glycine rich protein 2 exacerbates vascular fibrosis in pulmonary hypertension through the nuclear translocation of yes-associated protein and transcriptional coactivator with PDZ-binding motif

  • Toxicol Appl Pharmacol. 2022 Dec 15:457:116319. doi: 10.1016/j.taap.2022.116319.
Xinghe Chen 1,  Xiaozhen Wei 2,  Saijie Ma 3,  Huating Xie 3,  Sirui Huang 3,  Mengge Yao 2,  Li Zhang 4
Affiliations

Affiliations

  • 1 Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Department of Pediatric Surgery, The First Affiliated Hospital of Fujian Medical University, Fujian Medical University, Fuzhou, China.
  • 2 Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, China; The Key Laboratory of Fujian Province Universities on Ion Channel and Signal Transduction in Cardiovascular Diseases, Department of Physiology and Pathophysiology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
  • 3 The Key Laboratory of Fujian Province Universities on Ion Channel and Signal Transduction in Cardiovascular Diseases, Department of Physiology and Pathophysiology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
  • 4 Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, China; The Key Laboratory of Fujian Province Universities on Ion Channel and Signal Transduction in Cardiovascular Diseases, Department of Physiology and Pathophysiology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. Electronic address: zhangli@fjmu.edu.cn.
PMID: 36414118 DOI: 10.1016/j.taap.2022.116319
Abstract

Pulmonary hypertension (PH) is a serious Cardiovascular Disease with a poor prognosis and high mortality. The pathogenesis of PH is complex, and the main pathological changes in PH are abnormal hypertrophy and vessel stiffness. Cysteine and glycine rich protein 2 (Csrp2), a member of the LIM-only family plays a key role in the response to vascular injury. However, its roles in vascular fibrosis and PH have not been clarified. Therefore, this study aimed to investigate whether Csrp2 can promote vascular fibrosis and to further explore the possible mechanisms. Csrp2 expression was increased in both the pulmonary vasculature of rats with PH and hypoxic pulmonary vascular smooth muscle cells (PASMCs). Hypoxia activated TGF-β1 and its downstream effector, SP1. Additionally, hypoxia activated the ROCK pathway and inhibited KLF4 expression. Silencing SP1 and overexpressing KLF4 reversed the hypoxia-induced increase in Csrp2 expression. Csrp2 knockdown decreased the expression of extracellular matrix (ECM) proteins and inhibited the nuclear translocation and expression of YAP/TAZ in hypoxic PASMCs. These results indicate that hypoxia induces Csrp2 expression through the TGF-β1/SP1 and ROCK/KLF4 pathways. Elevated Csrp2 promoted the nuclear translocation and expression of YAP/TAZ, leading to vascular fibrosis and the development of PH.

Keywords

Csrp2; Pulmonary artery smooth muscle cells; ROCK/KLF4; TGF-β1/SP1; YAP/TAZ.

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