(525.8) FXR1 Decreases Blood Pressure by Regulating Vascular Contractility

Poster Board Number: D8
Introduction:

Amanda St. Paul (Temple University School of Medicine), Kyle Preston (Temple University School of Medicine), Cali Corbett (Temple University School of Medicine, Temple University School of Medicine), Tani Leigh (Temple University School of Medicine), Sheri Kelemen (Temple University School of Medicine), Rachael Okune (Temple University School of Medicine), Satoru Eguchi (Temple University School of Medicine), Dale Haines (Temple University School of Medicine), Michael Autieri (Temple University School of Medicine)

Introduction:  Hypertension is a major risk factor for cardiovascular disease and stroke. Optimally treated hypertensive patients still have a 50% greater cardiovascular risk than untreated normotensive subjects. Despite current medication, half a million deaths in the United States include hypertension as a primary contributing cause in 2018 presenting a need for additional targets. Vascular smooth muscle cells (VSMCs) are the fulcrum of vascular disease, particularly hypertension. VSMCs play a critical role in vascular contractility and the regulation of blood pressure. Fragile X-related protein (FXR1) is a muscle-enhanced RNA binding protein and we previously found siRNA knock down of FXR1 increases inflammatory mRNA stability. Overexpression of FXR1 decreases inflammatory mRNA stability in VSMC. Little is known concerning FXR1 protein binding partners and its role in vascular disease. The specific aim of this study is to test the hypothesis that FXR1 regulates vascular contractility by RNA stability and protein interactions.

Results:  We generated a novel, VSMC-specific FXR1 conditional knock out mouse (FXR1VSMC/VSMC) in order to establish an in vivo role of FXR1 in vascular disease. Preliminary data indicates that these mice show decreased diastolic (P lt; 0.05) blood pressure at baseline compared to controls. Gene ontology of RNA immuno-precipitation sequencing analysis in human VSMCs identified that FXR1 binds to mRNA that participate in VSMC contractility and regulation of blood pressure- related pathways. Although considered an RNA stability protein, mass-spectrometry identified that FXR1 interacts with proteins related to contractile processes such as cell migration, adhesion and stress fiber formation. FXR1 depletion in human VSMCs decreases mRNA abundance of contractile machinery. Future studies will determine the effect of FXR1 depletion on mRNA stability of these transcripts. Additionally, siRNA knock down of FXR1 decreased VSMC adhesion, migration and collagen gel contraction corroborating in vivo observations. 

Conclusion:  These data are the first to suggest FXR1 regulates blood pressure and vascular contractility potentially by two mechanisms: mRNA stability and functional activity by protein-protein interactions. The findings support FXR1 activity may represent a target for therapeutic invention to regulate blood pressure.

This work was supported by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health R01 HL141108 and R01 HL117724 to M.V. Autieri.