Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension
Takeshi Masaki, Makoto Okazawa, Ryotaro Asano, Tadakatsu Inagaki, Tomohiko Ishibashi, Akiko Yamagishi, Saori Umeki-Mizushima, Manami Nishimura, Yusuke Manabe, Hatsue Ishibashi‐Ueda, Manabu Shirai, Hirotsugu Tsuchimochi, James T. Pearson, Atsushi Kumanogoh, Yasushi Sakata, Takeshi Ogo, Tadamitsu Kishimoto, Yoshikazu Nakaoka
Abstract
Significance Inflammatory signals are thought to be crucial for the pathogenesis of PAH; however, the underlying mechanism is still largely unknown. In this study, we demonstrate that AHR makes a causal contribution to the pathogenesis of PAH, activating a focal inflammatory response in the lungs and promoting infiltration of immune cells from the bone marrow. Furthermore, we found that PAH patients with higher AHR agonistic activity in sera are more susceptible to severe clinical events than those with lower activity. Because conventional therapy for pulmonary hypertension targeting pulmonary artery vasodilation has limited efficacy against severe PAH, the AHR-signaling pathway represents a promising therapeutic target for PAH. In addition, AHR agonistic activity in serum represents a biomarker for PAH.