Upregulation of Angiomotin-Like 2 Ameliorates Experimental Pulmonary Arterial Hypertension by Inactivating YAP1 Signaling

• Published in: Journal of cardiovascular pharmacology Vol. 84; no. 3; p. 356
• Main Authors: Deng, Jizhao, Yang, Guang, Zhong, Nier, Liang, Lei, Chen, Haichao
• Format: Journal Article
• Language: English
• Published: United States 01.09.2024
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Angiomotins; Animals; Arterial Pressure - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Disease Models, Animal; Hypertrophy, Right Ventricular - metabolism; Hypertrophy, Right Ventricular - pathology; Hypertrophy, Right Ventricular - physiopathology; Male; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Muscle, Smooth, Vascular - physiopathology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Phenotype; Phosphorylation; Pulmonary Arterial Hypertension - drug therapy; Pulmonary Arterial Hypertension - metabolism; Pulmonary Arterial Hypertension - pathology; Pulmonary Arterial Hypertension - physiopathology; Pulmonary Artery - drug effects; Pulmonary Artery - metabolism; Pulmonary Artery - pathology; Pulmonary Artery - physiopathology; Rats; Rats, Sprague-Dawley; Signal Transduction; Up-Regulation; Vascular Remodeling - drug effects; Ventricular Function, Right - drug effects; YAP-Signaling Proteins - metabolism
• ISSN: 1533-4023
• DOI: 10.1097/FJC.0000000000001606

Angiomotin-like 2 (AMOTL2) is related to numerous physiological and pathological conditions by affecting signal transduction. However, whether AMOTL2 is linked to pulmonary arterial hypertension (PAH) has not been addressed. This work aimed to investigate the potential role of AMOTL2 in PAH. A decrease in AMOTL2 abundance was observed in the lungs of PAH rats. The upregulation of AMOTL2 significantly decreased right ventricle systolic pressure and right ventricular hypertrophy in PAH rats. Overexpression of AMOTL2 also led to a noteworthy decrease in vascular wall thickness, pulmonary artery area, and collagen deposition in rats with PAH. AMOTL2 was downregulated in hypoxia-stimulated pulmonary arterial smooth muscle cells (PASMCs). Moreover, AMOTL2 overexpression impeded hypoxia-evoked proliferation, migration, and phenotypic transformation in rat PASMCs. Mechanistic investigation revealed that Yes-associated protein 1 (YAP1) activation in PAH rats or hypoxia-stimulated PASMCs was markedly inhibited by AMOTL2 overexpression, which was associated with increased large tumor suppressor 1/2 phosphorylation. The inhibition of large tumor suppressor 1/2 reversed the AMOTL2-mediated inactivation of YAP1. Restoring the activity of YAP1 reversed the inhibitory effect of AMOTL2 on hypoxia-evoked proliferation, migration, and phenotypic transformation of PASMCs. Collectively, these results suggest that AMOTL2 can ameliorate PAH in a rat model by interfering with pulmonary arterial remodeling via the inactivation of YAP1 signaling. Our work indicates that AMOTL2 may be a candidate target for novel drug development for the treatment of PAH.