Journal article
Non‐canonical IKB kinases regulate YAP/TAZ and pathological vascular remodeling behaviors in pulmonary artery smooth muscle cells
Physiological reports, Vol.12(7), pp.e15999-n/a
04/2024
DOI: 10.14814/phy2.15999
PMCID: PMC11014870
PMID: 38610069
Abstract
Pulmonary arterial hypertension (PAH) causes pulmonary vascular remodeling, increasing pulmonary vascular resistance (PVR) and leading to right heart failure and death. Matrix stiffening early in the disease promotes remodeling in pulmonary artery smooth muscle cells (PASMCs), contributing to PAH pathogenesis. Our research identified YAP and TAZ as key drivers of the mechanobiological feedback loop in PASMCs, suggesting targeting them could mitigate remodeling. However, YAP/TAZ are ubiquitously expressed and carry out diverse functions, necessitating a cell‐specific approach. Our previous work demonstrated that targeting non‐canonical IKB kinase TBK1 reduced YAP/TAZ activation in human lung fibroblasts. Here, we investigate non‐canonical IKB kinases TBK1 and IKKε in pulmonary hypertension (PH) and their potential to modulate PASMC pathogenic remodeling by regulating YAP/TAZ. We show that TBK1 and IKKε are activated in PASMCs in a rat PH model. Inflammatory cytokines, elevated in PAH, activate these kinases in human PASMCs. Inhibiting TBK1/IKKε expression/activity significantly reduces PAH‐associated PASMC remodeling, with longer‐lasting effects on YAP/TAZ than treprostinil, an approved PAH therapy. These results show that non‐canonical IKB kinases regulate YAP/TAZ in PASMCs and may offer a novel approach for reducing vascular remodeling in PAH.
Details
- Title: Subtitle
- Non‐canonical IKB kinases regulate YAP/TAZ and pathological vascular remodeling behaviors in pulmonary artery smooth muscle cells
- Creators
- Aja Aravamudhan - Mayo Clinic in FloridaPaul B. Dieffenbach - Brigham and Women's HospitalKyoung Moo Choi - Mayo Clinic in FloridaPatrick A. Link - Mayo Clinic in FloridaJeffrey A. Meridew - Mayo Clinic in FloridaAndrew J. Haak - Mayo Clinic in FloridaLaura E. Fredenburgh - Brigham and Women's HospitalDaniel J. Tschumperlin - Mayo Clinic in Florida
- Resource Type
- Journal article
- Publication Details
- Physiological reports, Vol.12(7), pp.e15999-n/a
- DOI
- 10.14814/phy2.15999
- PMID
- 38610069
- PMCID
- PMC11014870
- NLM abbreviation
- Physiol Rep
- ISSN
- 2051-817X
- eISSN
- 2051-817X
- Number of pages
- 16
- Grant note
- Foundation for the National Institutes of Health (FNIH) (5R01HL137366‐04; K08 HL‐143197; HL105355; HL158018; HL153026) American Heart Association (AHA) (20POST35210650; 17GRNT33660449)
- Language
- English
- Date published
- 04/2024
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Craniofacial Anomalies Research Center
- Record Identifier
- 9984948144402771
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