Role of secretory protein GREM1 in systemic-to-pulmonary shunt associated pulmonary arterial hypertension
- VernacularTitle:分泌型蛋白质 GREM1 在体-肺分流性肺动脉高压中的作用
- Author:
Xu LIU
1
,
2
;
Hongyu DENG
2
;
Ping ZHOU
3
Author Information
1. Department of Ultrasound Diagnosis of The Third Xiangya Hospital of Central South University, Changsha, 410013, P.R.China;
2. Department of Ultrasound of Hunan Cancer Hospital, Changsha, 410013, P.R.China
3. Department of Ultrasound Diagnosis of The Third Xiangya Hospital of Central South University, Changsha, 410013, P.R.China
- Publication Type:Journal Article
- Keywords:
Congenital heart disease;
systemic-to-pulmonary shunt;
pulmonary arterial hypertension;
pulmonary vascular remodeling;
bone morphogenetic protein antagonist
- From:
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery
2021;28(04):479-487
- CountryChina
- Language:Chinese
-
Abstract:
Objective To explore the possibility that GREM1, a bone morphogenetic protein (BMP) antagonist, is a mechanical explanation for BMP signal suppression in congenital heart disease associated pulmonary arterial hypertension (CHD/PAH) patients. Methods Systemic-to-pulmonary shunt induced PAH was surgically established in rats. At the postoperative 12th week, right heart catheterization and echocardiography evaluation were performed to evaluate hemodynamic indexes and morphology of right heart system. Right heart hypotrophy index and pulmonary vascular remodeling were evaluated. Changes of BMP signal pathway related proteins and GREM1 in lungs and plasma GREM1 concentration were detected. The effect of GREM1 on the proliferation and apoptosis of pulmonary arterial endothelial cells (PAECs) was also explored. Results The hypertensive status was successfully reproduced in rats with systemic-to-pulmonary shunt model. BMP signal pathway was suppressed but GREM1 was up-regulated with no change in hypoxia inducible factor-1 in lungs exposed to systemic-to-pulmonary shunt, while this trend was reversed by systemic-to-pulmonary shunt correction (P<0.05). Immunohistochemical staining demonstrated enhanced staining of GREM1 in remodeled pulmonary arteries. In vitro experiments found that BMP signal was down-regulated but GREM1 expression and secretion were up-regulated in proliferative PAECs (P<0.05). Furthermore, BMP2 significantly inhibited PAECs proliferation and promoted PAECs apoptosis (P<0.05), which could be antagonized by GREM1. In addition, plasma level of GREM1 in rats with systemic-to-pulmonary shunt was also increased and positively correlated with pulmonary hemodynamic indexes. Conclusion Systemic-to-pulmonary shunt induces the up-regulation of GREM1 in lungs, which promotes pulmonary vascular remodeling via antagonizing BMP cascade. These results present a new mechanical explanation for BMP pathway suppression in lungs of CHD/PAH patients.
