CALL FOR PAPERS Pathophysiology of Hypertension Role of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension

Nitta CH, Osmond DA, Herbert LM, Beasley BF, Resta TC, Walker BR, Jernigan NL. Role of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 306: H41–H52, 2014. First published November 1, 2013; doi:10.1152/ajpheart.00269.2013.—Chronic hypoxia (CH) associated with respiratory disease results in elevated pulmonary vascular intracellular Ca concentration, which elicits enhanced vasoconstriction and promotes vascular arterial remodeling and thus has important implications in the development of pulmonary hypertension (PH). Store-operated Ca entry (SOCE) contributes to this elevated intracellular Ca concentration and has also been linked to acute hypoxic pulmonary vasoconstriction (HPV). Since our laboratory has recently demonstrated an important role for acid-sensing ion channel 1 (ASIC1) in mediating SOCE, we hypothesized that ASIC1 contributes to both HPV and the development of CH-induced PH. To test this hypothesis, we examined responses to acute hypoxia in isolated lungs and assessed the effects of CH on indexes of PH, arterial remodeling, and vasoconstrictor reactivity in wild-type (ASIC1 / ) and ASIC1 knockout (ASIC1 / ) mice. Restoration of ASIC1 expression in pulmonary arterial smooth muscle cells from ASIC1 / mice rescued SOCE, confirming the requirement for ASIC1 in this response. HPV responses were blunted in lungs from ASIC1 / mice. Both SOCE and receptormediated Ca entry, along with agonist-dependent vasoconstrictor responses, were diminished in small pulmonary arteries from control ASIC / mice compared with ASIC / mice. The effects of CH to augment receptor-mediated vasoconstrictor and SOCE responses in vessels from ASIC1 / mice were not observed after CH in ASIC1 / mice. In addition, ASIC1 / mice exhibited diminished right ventricular systolic pressure, right ventricular hypertrophy, and arterial remodeling in response to CH compared with ASIC1 / mice. Taken together, these data demonstrate an important role for ASIC1 in both HPV and the development of CH-induced PH.