Mechanosensitive microRNAs-role in endothelial responses to shear stress and redox state

Abstract

Endothelial functions are highly regulated by imposed shear stress in vivo. The characteristics of shear stress determine mechanotransduction events that regulate phenotypic outcomes including redox and inflammatory states. Recent data indicate that microRNAs (miRs) in vascular endothelial cells play an essential role in shear stress-regulated endothelial responses. More specifically, atheroprotective pulsatile flow (PS) induces miRs that inhibit mediators of oxidative stress and inflammation while promoting those involved in maintaining vascular homeostasis. Conversely, oscillatory flow (OS) elicits the opposing networks. This is exemplified by the PS-responsive transcription factor Krüppel-like factor 2 (KLF2), which regulates miR expression but is also regulated by OS-sensitive miRs to ultimately regulate the oxidative and inflammatory state of the endothelium. In this review, we outline important findings demonstrating the multifaceted roles of shear stress-regulated miRs in endothelial redox and inflammatory balance. Furthermore, we discuss the use of algorithms in deciphering signaling networks differentially regulated by PS and OS.

Keywords: ACE; AMP-activated protein kinase; AMPK; CDK4; ChIP; EC; ELISA; Endothelium; FIRM; Framework for the Inference of Regulation by MiRs; Free radicals; GPx; HDAC; ICAM-1; IL; ITGA5; Inflammation; JNK; KLF2; Krüppel-like factor 2; MAP3K7; MEF2; MiR; NADPH oxidase; NF-κB; NOX; OS; Oxidative stress; PAK; PS; ROCK1; ROS; Rho-associated, coiled-coil-containing protein kinase 1; SIRT1; SOD; Shear stress; TrxR2; VCAM-1; angiotensin-converting enzyme; c-Jun N-terminal kinase; chromatin immunoprecipitation; cyclin-dependent kinase 4; eNOS; endothelial cell; endothelial nitric oxide synthase; enzyme-linked immunosorbent assay; glutathione peroxidase; histone deacetylase; integrin α5; intercellular adhesion molecule 1; interleukin; miR; microRNA; mitogen-activated protein kinase kinase kinase 7; myocyte enhancer factor-2; nuclear factor κ-light-chain-enhancer of activated B cells; oscillatory shear; p21-activated kinase; pulsatile shear; reactive oxygen species; silent mating type information regulation 2 homolog 1; superoxide dismutase; thioredoxin-dependent peroxidase; vascular cell adhesion protein 1; β-transducin repeat-containing E3 ubiquitin protein ligase; βTRC.