Abstract 13129: FXR1 Regulates Blood Pressure by Altering Vascular Contractility

Abstract

Introduction: Hypertension is a major risk factor for heart disease and stroke. Despite current medication, half a million deaths in the United States include hypertension as a primary contributing cause, presenting a need for additional targets. Vascular smooth muscle cells (VSMCs) play a central role in vascular contractility and the regulation of blood pressure (BP). Fragile X-related protein (FXR1) is a muscle-enhanced RNA binding protein. Knock down of FXR1 increases inflammatory mRNA stability, and overexpression of FXR1 decreases inflammatory mRNA stability in VSMC. FXR1 knock out mice have a muscle-specific phenotype. While little is known concerning FXR1 protein binding partners and its role in vascular disease, its muscle-enhanced expression suggests a specialized role in VSMC. The specific aim of this study is to test the hypothesis that FXR1 regulates vascular contractility by regulation of RNA stability and protein-protein interactions. Results: To characterize 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 are hypotensive as they show decreased systolic (P < 0.001) and diastolic (P < 0.01) BP, and increased resting heart rate (P < 0.05) at baseline compared to controls. To identify mRNA binding targets, gene ontology of RNA immuno-precipitation sequencing analysis (RIPseq) in human VSMCs identified that FXR1 preferentially binds to mRNA that participate in VSMC contractility and regulation of BP. Although considered an RNA stability protein, mass-spectrometry identified that FXR1 interacts with proteins related to VSMC contractile processes such as cell migration, adhesion and stress fiber formation. At a functional level, siRNA knock down of FXR1 decreased VSMC migration and collagen gel contraction corroborating in vivo observations. Conclusion: These data show that deletion of FXR1 decrease BP and VSMC contractile processes. They are the first to suggest FXR1 regulates BP 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 BP.