Send to

Choose Destination
Circulation. 2018 Oct 2. doi: 10.1161/CIRCULATIONAHA.118.034615. [Epub ahead of print]

LMO7 is a Negative Feedback Regulator of TGF-β Signaling and Fibrosis.

Author information

Medicine, Yale University, UNITED STATES.
Yale University School of Medicine and Yale Cardiovascular Research Group, Yale University, UNITED STATES.
Medicine (Cardiology) and Pharmacology, Yale School of Medicine, UNITED STATES.
Surgery, Yale University School of Medicine, UNITED STATES.
Medicine and Pharmacology, Yale University, UNITED STATES.
Biostatistics, Yale University, UNITED STATES.
Biomedical Engineering, Yale University, UNITED STATES.
Internal Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, UNITED STATES.
Internal Medicine, Yale Section of Pulmonology, UNITED STATES.
Pathology, Yale University, UNITED STATES.
Biostatistics, Yale School of Public Health, UNITED STATES.
Centers for Metabolic Disease Research, Temple University School of Medicine, UNITED STATES.
Internal Medicine, Yale University School of Medicine, UNITED STATES.



Vascular smooth muscle cells (SMC) synthesize extracellular matrix (ECM) that contributes to tissue remodeling following revascularization interventions. The cytokine transforming growth factor-β (TGF-β) is induced upon tissue injury and regulates tissue remodeling and wound healing, but dysregulated signaling results in excess ECM deposition and fibrosis. The LIM domain protein LMO7 is a TGF-β target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown.


We employ carotid ligation and femoral artery denudation models in mice with global or inducible smooth muscle-specific deletion of LMO7, and knockout, knockdown, overexpression, and mutagenesis approaches in mouse and human SMC, and human arteriovenous fistula (AVF) and cardiac allograft vasculopathy (CAV) samples to assess the role of LMO7 in neointima and fibrosis.


We demonstrate that LMO7 is induced post-injury and by TGF-β in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-β signaling, ECM deposition and proliferation in vascular injury models. LMO7 loss of function in human and mouse SMC enhanced ECM protein expression at baseline and following TGF-β treatment. TGF-β neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-β signaling by inducing expression of Tgfb1 mRNA, TGF-β protein, αv and β3 integrins that promote activation of latent TGF-β, and downstream effectors pSMAD3 and CTGF. Mechanistically, the LMO7 LIM domain interacts with AP-1 transcription factor subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting AP-1-dependent TGF-β autoinduction. Importantly, preliminary studies suggest that LMO7 is upregulated in human intimal hyperplastic arteriovenous fistula (AVF) and cardiac allograft vasculopathy (CAV) samples, and inversely correlates with pSMAD3 in CAV.


LMO7 is induced by TGF-β and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-β pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.



Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center