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ORMDL3 expression in ASM regulates hypertrophy, hyperplasia via TPM1 and TPM4, and contractility
Alexa K Pham1, Marina Miller1, Peter Rosenthal1
1Department of Medicine, University of California San Diego, La Jolla, California, USA.
JCI Insight
|March 4, 2021
Summary
ORM1-like 3 (ORMDL3) expression in airway smooth muscle (ASM) causes ASM cells to grow and contract more. This may explain how ORMDL3 contributes to childhood asthma and airway hyperreactivity.
Area of Science:
- Pulmonary Medicine
- Genetics
- Cell Biology
Background:
- ORM1-like 3 (ORMDL3) is genetically linked to childhood asthma.
- The role of ORMDL3 specifically in airway smooth muscle (ASM) function is not well understood.
Purpose of the Study:
- To investigate the impact of selective ORMDL3 expression in ASM on ASM function and airway hyperreactivity (AHR).
Main Methods:
- Generated transgenic mice (hORMDL3Myh11eGFP-cre) for selective ORMDL3 expression in ASM.
- Conducted in vitro studies on isolated ASM cells (hypertrophy, hyperplasia, contractility, Ca2+ signaling).
- Performed in vivo studies to assess AHR in transgenic mice.
Main Results:
- ORMDL3 expression induced ASM cell hypertrophy, hyperplasia, and increased contractility in vitro.
- Increased intracellular Ca2+ levels and Orai1 channels were observed in ORMDL3-expressing ASM.
- Transgenic mice exhibited spontaneous increases in ASM and AHR in vivo.
Conclusions:
- Selective ORMDL3 expression in ASM leads to cellular changes and increased contractility.
- These ASM alterations may contribute to the development of AHR in childhood-onset asthma.
- ORMDL3's role in ASM dysfunction provides a potential mechanism linking chromosome 17q12-21 linkage to asthma pathogenesis.
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