title: Notch activation of Ca2+-sensing receptor mediates hypoxia-induced pulmonary hypertension.
abstract: A recent study from our group demonstrated that the Ca2+-sensing receptor (CaSR) was upregulated and that the extracellular Ca2+-induced increase in the cytosolic Ca2+concentration [Ca2+]cytwas enhanced in pulmonary arterial smooth muscle cells (PASMCs) from patients with idiopathic pulmonary arterial hypertension. Here, we examined whether hypoxia-induced activation of Notch signaling leads to the activation and upregulation of CaSR in hypoxia-induced pulmonary hypertension (HPH). The activation of Notch signaling with Jag-1, a Notch ligand, can activate the function and increase the expression of CaSR in acute and chronic hypoxic PASMCs. Downregulation of Notch3 with a siRNA attenuates the extracellular Ca2+-induced increase in [Ca2+]cytand the increase in hypoxia-induced PASMC proliferation in acute hypoxic rat PASMCs. Furthermore, we tested the prevention and rescue effects of a γ-secretase inhibitor (DAPT) in HPH rats. For the Jag-1-treated group, right ventricular systolic pressure (RVSP), right heart hypertrophy (RV/LV+S ratio), and the level of right ventricular myocardial fibrosis were higher than the hypoxia alone group. Meanwhile, DAPT treatment prevented and rescued pulmonary hypertension in HPH rats. The Notch activation of CaSR mediates hypoxia-induced pulmonary hypertension. Understanding the new molecular mechanisms that regulate [Ca2+]cytand PASMC proliferation is critical to elucidating the pathogenesis of HPH and the development of novel therapies for pulmonary hypertension.
authors: Department of Medicine, Respiratory, Emergency and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors: Qiang
authors: Q
authors: Guo
authors: Department of Medicine, Respiratory, Emergency and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors: Hua
authors: H
authors: Xu
authors: Department of Medicine, Respiratory, Emergency and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors: Xinjing
authors: X
authors: Yang
authors: Department of Medicine, Respiratory, Emergency and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors: Daguo
authors: D
authors: Zhao
authors: Department of Medicine, Respiratory, Emergency and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors: Shenlang
authors: S
authors: Liu
authors: Department of Medicine, Respiratory, Emergency and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors: Xue
authors: X
authors: Sun
authors: Department of Medicine, Respiratory, Emergency and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors: Jian-An
authors: JA
authors: Huang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D003959:Diamines / Q000494:pharmacology / Q000627:therapeutic use; D005355:Fibrosis / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000150:complications*; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C000612000:24-diamino-5-phenylthiazole; D003959:Diamines; D044169:Receptors, Calcium-Sensing; D051880:Receptors, Notch; D013844:Thiazoles; D053829:Amyloid Precursor Protein Secretases; D002118:Calcium