A urotensin II receptor antagonist, KR36676, decreases vascular remodeling and inflammation in experimental pulmonary hypertension.
The pathophysiological implications of binding of urotensin II (U-II) to urotensin II receptor (UT) in pulmonary arterial hypertension (PAH) have been proposed recently. Besides high expression of U-II in experimental models and patients with PAH, U-II has been shown to increase proliferation of pulmonary vascular smooth muscle cells and inflammatory responses, which were critical for PAH pathophysiology. However, the direct role of the urotensinergic system in the pathogenesis of PAH is yet to be understood. The aim of the present study was to determine whether a novel UT antagonist, KR36676, attenuates the pathophysiological progression of PAH in an animal model of PAH. PAH was induced by a single subcutaneous injection of monocrotaline (MCT, 60mg/kg) in rats. All the animals received KR36676 (30mg/kg/day) or vehicle by oral gavage. Three weeks after MCT-injection, changes in hemodynamic parameters, extent of right ventricular hypertrophy, fibrosis and pulmonary vascular remodeling, and degree of protein expression were determined. Oral administration of KR36676 effectively decreased the MCT-induced increase in right ventricular systolic pressure, hypertrophy and fibrosis. Furthermore, wall thickness of pulmonary arterioles, proliferation of pulmonary vascular cells, and inflammatory response significantly decreased in the KR36676-treated group following MCT injection compared to that in the MCT-treated vehicle group. These preventive effects of KR36676 are mediated, at least in part, by suppression of ERK1/2 and NF-κB signaling pathways. The novel UT antagonist, KR36676, effectively prevented MCT-induced PAH progression and pulmonary vascular remodeling in rat model. Our findings support the therapeutic efficacy of UT antagonist in PAH prevention and elucidate the possible underlying mechanisms of action.
Research Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
Jeong Hyun
JH
Lee
Research Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea.
Byung Kil
BK
Park
Research Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 34113 Daejeon, Republic of Korea.
Kwang-Seok
KS
Oh
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 34113 Daejeon, Republic of Korea; Research Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
Kyu Yang
KY
Yi
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 34113 Daejeon, Republic of Korea; Research Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
Chae Jo
CJ
Lim
Research Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
Ho Won
HW
Seo
Research Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea. Electronic address: bhlee@krict.re.kr.
Byung Ho
BH
Lee
D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use*; D003094:Collagen / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D016686:Monocrotaline; D016328:NF-kappa B / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D066253:Vascular Remodeling / Q000187:drug effects
D000081:Acetamides; D000893:Anti-Inflammatory Agents; D048588:Benzoxazines; C000607772:KR36676; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; C473142:Uts2r protein, rat; D016686:Monocrotaline; D003094:Collagen
Hypertrophy; Monocrotaline; Pulmonary arterial hypertension; Urotensin II; Urotensin receptor antagonist; Vascular remodeling