Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension
Acid-sensing ion channel 1a (ASIC1a) is a voltage-independent, non-selective cation channel that conducts both Na+ and Ca2+. Activation of ASIC1a elicits plasma membrane depolarization and stimulates intracellular Ca2+-dependent signaling pathways in multiple cell types, including vascular smooth mu...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.989809/full |
| _version_ | 1797997261665337344 |
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| author | Selina M. Garcia Tracy R. Yellowhair Neil D. Detweiler Rosstin Ahmadian Lindsay M. Herbert Laura V. Gonzalez Bosc Thomas C. Resta Nikki L. Jernigan |
| author_facet | Selina M. Garcia Tracy R. Yellowhair Neil D. Detweiler Rosstin Ahmadian Lindsay M. Herbert Laura V. Gonzalez Bosc Thomas C. Resta Nikki L. Jernigan |
| author_sort | Selina M. Garcia |
| collection | DOAJ |
| description | Acid-sensing ion channel 1a (ASIC1a) is a voltage-independent, non-selective cation channel that conducts both Na+ and Ca2+. Activation of ASIC1a elicits plasma membrane depolarization and stimulates intracellular Ca2+-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 (TekCre-Asic1afl/fl). However, similar to global Asic1a knockout (Asic1a−/-) mice, mice with specific deletion of SM-Asic1a (MHCCreER-Asic1afl/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 MHCCreER-Asic1afl/fl mice with established pulmonary hypertension. CH-induced vascular remodeling was also significantly attenuated in pulmonary arteries from MHCCreER-Asic1afl/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. |
| first_indexed | 2024-04-11T10:30:16Z |
| format | Article |
| id | doaj.art-5b0acd1eae6c415191754f383d469cd3 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-11T10:30:16Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-5b0acd1eae6c415191754f383d469cd32022-12-22T04:29:26ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-10-01910.3389/fmolb.2022.989809989809Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertensionSelina M. GarciaTracy R. YellowhairNeil D. DetweilerRosstin AhmadianLindsay M. HerbertLaura V. Gonzalez BoscThomas C. RestaNikki L. JerniganAcid-sensing ion channel 1a (ASIC1a) is a voltage-independent, non-selective cation channel that conducts both Na+ and Ca2+. Activation of ASIC1a elicits plasma membrane depolarization and stimulates intracellular Ca2+-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 (TekCre-Asic1afl/fl). However, similar to global Asic1a knockout (Asic1a−/-) mice, mice with specific deletion of SM-Asic1a (MHCCreER-Asic1afl/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 MHCCreER-Asic1afl/fl mice with established pulmonary hypertension. CH-induced vascular remodeling was also significantly attenuated in pulmonary arteries from MHCCreER-Asic1afl/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.https://www.frontiersin.org/articles/10.3389/fmolb.2022.989809/fullvascular remodelingendotheliumproliferationmigrationright heart hypertrophy |
| spellingShingle | Selina M. Garcia Tracy R. Yellowhair Neil D. Detweiler Rosstin Ahmadian Lindsay M. Herbert Laura V. Gonzalez Bosc Thomas C. Resta Nikki L. Jernigan Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension Frontiers in Molecular Biosciences vascular remodeling endothelium proliferation migration right heart hypertrophy |
| title | Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension |
| title_full | Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension |
| title_fullStr | Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension |
| title_full_unstemmed | Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension |
| title_short | Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension |
| title_sort | smooth muscle acid sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension |
| topic | vascular remodeling endothelium proliferation migration right heart hypertrophy |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.989809/full |
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