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Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension.
- Source :
-
Frontiers in molecular biosciences [Front Mol Biosci] 2022 Oct 05; Vol. 9, pp. 989809. Date of Electronic Publication: 2022 Oct 05 (Print Publication: 2022). - Publication Year :
- 2022
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Abstract
- Acid-sensing ion channel 1a (ASIC1a) is a voltage-independent, non-selective cation channel that conducts both Na <superscript>+</superscript> and Ca <superscript>2+</superscript> . Activation of ASIC1a elicits plasma membrane depolarization and stimulates intracellular Ca <superscript>2+</superscript> -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 <superscript>Cre</superscript> - Asic1a <superscript>fl/fl</superscript> ). However, similar to global Asic1a knockout ( Asic1a <superscript>-/-</superscript> ) mice, mice with specific deletion of SM- Asic1a (MHC <superscript>CreER</superscript> - Asic1a <superscript>fl/fl</superscript> ) 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 <superscript>CreER</superscript> - Asic1a <superscript>fl/fl</superscript> mice with established pulmonary hypertension. CH-induced vascular remodeling was also significantly attenuated in pulmonary arteries from MHC <superscript>CreER</superscript> - Asic1a <superscript>fl/fl</superscript> mice. These findings were additionally supported by decreased CH-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) from Asic1a <superscript>-/-</superscript> 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.<br />Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.<br /> (Copyright © 2022 Garcia, Yellowhair, Detweiler, Ahmadian, Herbert, Gonzalez Bosc, Resta and Jernigan.)
Details
- Language :
- English
- ISSN :
- 2296-889X
- Volume :
- 9
- Database :
- MEDLINE
- Journal :
- Frontiers in molecular biosciences
- Publication Type :
- Academic Journal
- Accession number :
- 36275633
- Full Text :
- https://doi.org/10.3389/fmolb.2022.989809