Hypoxia decrease expression of cartilage oligomeric matrix protein to promote phenotype switching of pulmonary arterial smooth muscle cells

Abstract Extracellular matrix proteins play important roles in the development of pulmonary hypertension(pH). However, the role of Cartilage oligomeric matrix protein(COMP) in the development of hypoxia-induced pH is largely unknown. We tested the hypothesis that COMP deficiency induced by hypoxia leads to the phenotype switchingof pulmonary arterial smooth muscle cells (PASMCs). The expression of COMP decreased in a chronic hypoxia rat pH model ( P 0.05 ) and in PASMCs under hypoxia (3%O 2 ) ( P 0.05 ). The expressions of differentiated marker proteins reduced in the pulmonary arteries from 5 month old COMP −/− mice and in PASMCs under hypoxia or with the siRNA of COMP treatment under normoxia, but increased in PASMCs with adenovirus-increased COMP under hypoxia. The absorbance of cell counting kit-8 at 450 nm and the expressions of proliferating cell nuclear antigen(PCNA) and osteopontinincreased in PASMCs with the siRNA of COMP under normoxia ( P 0.05 ). PCNA and osteopontindecreased in PASMCs with adenovirus-increased COMP under hypoxia ( P 0.05 ). Additionally, the expression of bone morphogenetic protein receptor2 ( BMPR2) was reduced in COMP −/− mice ( P 0.01 ). Both mRNA and protein levels of bone morphogenetic protein 2(BMP2) were lower in PASMCs with the siRNA of COMP ( P 0.05 ). The protein level of BMP2 could be reversed by adenovirus-increased COMP under hypoxia ( P 0.05 ). These data suggest that COMP could normally have a protective role against PASMC phenotype switchingand maintain BMP2/ BMPR2signaling, and these protective actions could be lost as a result of hypoxia promoting a depletion of COMP.