Acid-sensing ion channel 1a (ASIC1a) is a voltage-independent, non-selective cation channel that simultaneously conducts Na+ and Ca2+. The activation of ASIC1a causes depolarization of the plasma membrane, stimulating Ca2+-dependent signaling pathways in various cell types, including vascular smooth muscle (SM) and endothelial cells (ECs). Previous studies have indicated that the increase in pulmonary vascular resistance accompanying chronic hypoxia (CH) induced pulmonary hypertension requires ASIC1a to induce enhanced pulmonary vascular contraction and vascular remodeling.
Both SM and EC dysfunction drive these processes; however, the involvement of ASIC1a in these different cell types is unknown. Using the Cre-LoxP system to generate cell-type-specific Asic1a knockout mice, this study tested the hypothesis that SM-Asic1a contributes to CH-induced pulmonary hypertension and vascular remodeling, while EC-Asic1a opposes the development of CH-induced pulmonary hypertension. In mice with specific deletion of EC-Asic1a (TekCre-Asic1afl/fl), the severity of pulmonary hypertension did not change. However, similar to global Asic1a knockout (Asic1a-/-) mice, mice with specific deletion of SM-Asic1a (MHCCreER-Asic1afl/fl) were protected from CH-induced pulmonary hypertension and right heart hypertrophy.
Furthermore, when SM-Asic1a was conditionally deleted in MHCCreER-Asic1afl/fl mice, pulmonary hypertension was reversed. In the pulmonary arteries of MHCCreER-Asic1afl/fl mice, CH-induced vascular remodeling was also significantly attenuated. Additionally, these findings were supported by the reduced proliferation and migration of CH-induced Asic1a-/- pulmonary arterial smooth muscle cells (PASMCs). Together, these data suggest that SM- rather than EC-Asic1a contributes to CH-induced pulmonary hypertension and vascular remodeling. Moreover, these studies provide evidence for the therapeutic potential of inhibiting ASIC1a to reverse pulmonary hypertension.
References:
Garcia SM, Yellowhair TR, Detweiler ND, Ahmadian R, Herbert LM, Gonzalez Bosc LV, Resta TC, Jernigan NL. Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension. Front Mol Biosci. 2022 Oct 5;9:989809. doi: 10.3389/fmolb.2022.989809. PMID: 36275633; PMCID: PMC9581175.
Editor | Quan
For reprints, submissions, etc., please contact the Mays Medical Administrator.
Keli @ Mays Medical (WeChat ID: medsci-)
