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Vital Roles of Gremlin-1 in Pulmonary Arterial Hypertension Induced by Systemic-to-Pulmonary Shunts.

Journal of the American Heart Association (2020-08-05)
Liukun Meng, Xiao Teng, Yao Liu, Chao Yang, Shengwei Wang, Wen Yuan, Jian Meng, Hongjie Chi, Lihua Duan, Xiaoyan Liu
RESUMEN

Background Heterozygous mutation in BMP (bone morphogenetic protein) receptor 2 is rare, but BMP cascade suppression is common in congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH); however, the underling mechanism of BMP cascade suppression independent of BMP receptor 2 mutation is unknown. Methods and Results Pulmonary hypertensive status observed in CHD-PAH was surgically reproduced in rats. Gremlin-1 expression was increased, but BMP cascade was suppressed, in lungs from CHD-PAH patients and shunted rats, whereas shunt correction retarded these trends in rats. Immunostaining demonstrated increased gremlin-1 was mainly in the endothelium and media of remodeled pulmonary arteries. However, mechanical stretch time- and amplitude-dependently stimulated gremlin-1 secretion and suppressed BMP cascade in distal pulmonary arterial smooth muscle cells from healthy rats. Under static condition, gremlin-1 significantly promoted the proliferation and inhibited the apoptosis of distal pulmonary arterial smooth muscle cells from healthy rats via BMP cascade. Furthermore, plasma gremlin-1 closely correlated with hemodynamic parameters in CHD-PAH patients and shunted rats. Conclusions Serving as an endogenous antagonist of BMP cascade, the increase of gremlin-1 in CHD-PAH may present a reasonable mechanism explanation for BMP cascade suppression independent of BMP receptor 2 mutation.

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Sigma-Aldrich
Anti-GAPDH antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Mouse Gremlin-1 ELISA Kit, for cell culture supernatants, plasma, and serum samples