Novel role for copper transport protein CTR1 in hypoxia induced pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is a serious disorder that leads to right heart failure. It is characterized by elevated pulmonary vascular resistance and high pulmonary arterial pressure due to sustained vasoconstriction and remodeling of the vascular wall. It is known that cellular copper (Cu) plays an important role in angiogenesis, remodeling of extracellular matrix, and defense against oxidative radical damage, but no study has related abnormal changes in Cu‐transport to the pathogenesis of PH. Preliminary studies from our lab indicate that in a chronic hypoxia mouse model of PH both, the Cu import protein CTR1 and the Cu export protein ATP7A, are up‐regulated in lung, while Cu,Zn‐SOD, involved in neutralizing superoxide radicals, is down‐regulated. Furthermore, hypoxia results in up‐regulation of LOX (Cu‐dependent lysyl oxidase) that plays an important role in crosslinking extracellular matrix collagen and elastin fibers. Similar observations are made in sub‐cultured pulmonary artery smooth muscle cells (PASMC) after 48 hours of hypoxia, or in the presence of cobalt, a hypoxia inducer. Our observations indicate that cellular Cu metabolism is sensitive to hypoxia through transcriptional regulation of CTR1 and may contribute to the development of pulmonary hypertension through increased reactive oxygen species (ROS) and LOX‐dependent vascular remodeling of adventitia.