Boosting Endothelial Autophagy by MicroRNA Delivery Quenches Vascular Inflammation
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Autophagy in endothelial cells is an emerging anti-inflammatory and atheroprotective mechanism. In this issue of Circulation Research, Pankratz et al1 describe the function of an endothelial-enriched microRNA, miR-100, that promotes autophagy through direct suppression of the autophagy inhibitors, mTOR (mammalian target of rapamycin) and Raptor. Furthermore, they demonstrate that miR-100 suppresses proinflammatory NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling and endothelial cell activation in an autophagy-dependent manner. Global inhibition of miR-100 in an in vivo model of atherosclerosis worsens disease while the opposite is the case when miR-100 mimetics are delivered intravenously. This study implies that therapeutics that can augment miR-100 levels in the endothelium will enhance autophagy and may be used to restrain vascular inflammation and atherogenesis. However, improvements in the specificity of microRNA delivery in vivo will be required to further test this concept because the authors also identify additional effects on cholesterol metabolism (albeit beneficial) in the livers of miR-100 mimetic-injected mice that seem to be autophagy dependent.
Article, see p 417
The activation of the endothelium and subsequent recruitment of circulating inflammatory cells into the vessel wall is a central driver of atherosclerotic disease. This chronic vascular inflammatory response is primarily orchestrated by the transcriptional induction of a network of adhesion molecules, cytokines, and chemokines through the activity of the transcription factor, NF-κB, which is activated downstream of cholesterol accumulation in the vessel wall, and in response to disturbed blood flow patterns. Identifying the mechanisms that control the activation of NF-κB may reveal new therapeutic targets to block disease progression. However, it is important to note that targeting this pathway may only be effective in particular cell types or at specific stages of disease. For example, although endothelial NF-κB is required for atherosclerotic progression,2 suppression of macrophage NF-κB paradoxically accelerates atherosclerosis. …