Therapeutic opportunities for intestinal angioectasia- targeting PPARγ and oxidative stress.

Recurrent and acute bleeding from intestinal tract angioectasia (AEC) presents a major challenge for clinical intervention. Current treatments are empiric, with frequent poor clinical outcomes. Improvements in understanding the pathophysiology of these lesions will help guide treatment. Using data from FDA's Adverse Event Reporting System (FAERS) we analyzed 12 million patient reports to identify drugs inversely correlated with GI-bleeding and potentially limiting AEC severity. FAERS analysis revealed that drugs used in diabetes and those targeting PPARγ-related mechanisms were associated with decreased AEC phenotypes (p < 0.0001). Electronic Health Records (EHR) at University of Cincinnati Hospital were analyzed to validate FAERS analysis. EHR data showed a 5.6% decrease in risk of AEC and associated phenotypes in patients on PPARγ agonists. Murine knockout models of AEC phenotypes were used to construct a gene-regulatory network of candidate drug targets and pathways, which revealed that wound healing, vasculature development and regulation of oxidative stress were impacted in AEC pathophysiology. Human colonic tissue was examined for expression differences across key pathway proteins, PPARγ, HIF1α, VEGF and TGFβ1. In vitro analysis of human AEC tissues showed lower expression of PPARγ and TGFβ1 compared to controls (0.55 ± 0.07 and 0.49 ± 0.05). NCBI GEO RNA-Seq data was analyzed to substantiate human tissue findings. This integrative discovery approach showing altered expression of key genes involved in oxidative stress and injury repair mechanisms presents novel insight into AEC etiology, which will improve targeted mechanistic studies and more optimal medical therapy for AEC.