Abstract 318: Fxr1 Regulates Vascular Contractility And Decreases Blood Pressure

Introduction: Hypertension is a major risk factor for cardiovascular disease and stroke. Optimally treated hypertensive patients have a 50% greater cardiovascular risk than untreated normotensive subjects presenting a need for additional targets. Vascular smooth muscle cells (VSMC) are the fulcrum of vascular disease, particularly hypertension. VSMC 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: Gene ontology of RNA immuno-precipitation sequencing analysis in human VSMC identified that FXR1 binds to mRNA that participate in VSMC contractility and regulation of blood pressure- related pathways. FXR1 depletion in human VSMC decreases mRNA abundance of contractile machinery such as RhoA, Cortactin, ARP2 and Dynactin. While 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. Additionally, siRNA knock down of FXR1 decreased VSMC adhesion, migration and collagen gel contraction. FXR1 depletion decreases CDC42 activation in VSMC. CDC42 is a small GTPase involved in cell morphology, adhesion and migration. In order to establish an in vivo role of FXR1 in vascular disease we generated a novel, VSMC-specific FXR1 conditional knock out mouse (FXR1 VSMC/VSMC ). Preliminary data indicates that these mice show decreased diastolic (P < 0.05) blood pressure at baseline compared to controls. 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. These findings suggest FXR1 as target for therapeutic intervention to regulate blood pressure.