Abstract 4925: TGF-β Downregulates PPARgamma Gene Expression in Pulmonary Arterial Smooth Muscle Cells (PASMCs): Novel Mechanism of Hypoxia-induced Pulmonary Vascular Remodeling
Introduction: Pharmacologic activation of PPARγ in lung has been shown to attenuate pulmonary arterial remodeling and fibrosis associated with hypoxic pulmonary hypertension. We previously have shown that transforming growth factor (TGF)- β plays a critical role in hypoxia-induced pulmonary vascular remodeling and fibrosis. The current study tested the novel hypotheses that endogenous PPARγ gene expression is downregulated in lung exposed to chronic hypoxia and in PASMCs treated with TGF-β.
In vivo: 10 wk old male Sprague-Dawley rats were exposed to 10% O2 for 2 wks. PPARγ protein levels in lung were assessed using Western blot analysis.
In vitro: Rat PASMCs were transfected with a plasmid including PPARγ promoter and a luciferase reporter gene and then exposed to TGF-β1 (1 ng/ml) for 24 hrs. PPARγ promoter activity and mRNA levels were assessed using luciferase activity and real time qRT-PCR analyses.
Results: 2-wk hypoxic exposure significantly decreased PPARγ protein levels in lung. TGF-β1 treatment decreased PPARγ promoter activity and mRNA levels in PASMCs (Figure⇓).
Conclusion: These provocative findings indicate that TGF-β inhibits expression of PPARγ, a putative endogenous anti-fibrogenic transcription factor, in PASMCs. This observation, coupled with the finding that chronic hypoxic exposure decreases PPARγ in lung, suggests that TGF-β-induced downregulation of PPARγ in PASMCs represents a novel mechanism of hypoxia-induced pulmonary vascular remodeling and fibrosis. The interaction between TGF-β and PPARγ signaling pathways at this level may play an important role in modulating the pro-fibrogenic response of lung to hypoxic exposure.
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).