| First Author | Garcia SM | Year | 2022 |
| Journal | Front Mol Biosci | Volume | 9 |
| Pages | 989809 | PubMed ID | 36275633 |
| Mgi Jnum | J:350260 | Mgi Id | MGI:7662466 |
| Doi | 10.3389/fmolb.2022.989809 | Citation | Garcia SM, et al. (2022) Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension. Front Mol Biosci 9:989809 |
| abstractText | Acid-sensing ion channel 1a (ASIC1a) is a voltage-independent, non-selective cation channel that conducts both Na(+) and Ca(2+). Activation of ASIC1a elicits plasma membrane depolarization and stimulates intracellular Ca(2+)-dependent signaling pathways in multiple cell types, including vascular smooth muscle (SM) and endothelial cells (ECs). Previous studies have shown that increases in pulmonary vascular resistance accompanying chronic hypoxia (CH)-induced pulmonary hypertension requires ASIC1a to elicit enhanced pulmonary vasoconstriction and vascular remodeling. Both SM and EC dysfunction drive these processes; however, the involvement of ASIC1a within these different cell types is unknown. Using the Cre-LoxP system to generate cell-type-specific Asic1a knockout mice, we tested the hypothesis that SM-Asic1a contributes to CH-induced pulmonary hypertension and vascular remodeling, whereas EC-Asic1a opposes the development of CH-induced pulmonary hypertension. The severity of pulmonary hypertension was not altered in mice with specific deletion of EC-Asic1a (Tek(Cre)-Asic1a (fl/fl)). However, similar to global Asic1a knockout (Asic1a (-/-)) mice, mice with specific deletion of SM-Asic1a (MHC(CreER)-Asic1a (fl/fl)) were protected from the development of CH-induced pulmonary hypertension and right heart hypertrophy. Furthermore, pulmonary hypertension was reversed when deletion of SM-Asic1a was initiated in conditional MHC(CreER)-Asic1a (fl/fl) mice with established pulmonary hypertension. CH-induced vascular remodeling was also significantly attenuated in pulmonary arteries from MHC(CreER)-Asic1a (fl/fl) mice. These findings were additionally supported by decreased CH-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) from Asic1a (-/-) mice. Together these data demonstrate that SM-, but not EC-Asic1a contributes to CH-induced pulmonary hypertension and vascular remodeling. Furthermore, these studies provide evidence for the therapeutic potential of ASIC1a inhibition to reverse pulmonary hypertension. |
