Rationale

In atherosclerotic lesions, synthetic smooth muscle cells (sSMCs) induce aberrant microRNA (miR) profiles in endothelial cells (ECs) under flow stagnation. Increase in shear stress induces favorable miR modulation to mitigate sSMC-induced inflammation.

Objective

To address the role of miRs in sSMC-induced EC inflammation and its inhibition by shear stress.

Methods and results

Coculturing ECs with sSMCs under static condition causes initial increases of 4 anti-inflammatory miRs (146a/708/451/98) in ECs followed by decreases below basal levels at 7 days; the increases for miR-146a/708 peaked at 24 hours and those for miR-451/98 lasted for only 6 to 12 hours. Shear stress (12 dynes/cm(2)) to cocultured ECs for 24 hours augments these 4 miR expressions. In vivo, these 4 miRs are highly expressed in neointimal ECs in injured arteries under physiological levels of flow, but not expressed under flow stagnation. MiR-146a, miR-708, miR-451, and miR-98 target interleukin-1 receptor-associated kinase, inhibitor of nuclear factor-κB kinase subunit-γ, interleukin-6 receptor, and conserved helix-loop-helix ubiquitous kinase, respectively, to inhibit nuclear factor-κB signaling, which exerts negative feedback control on the biogenesis of these miRs. Nuclear factor-E2-related factor (Nrf)-2 is critical for shear-induction of miR-146a in cocultured ECs. Silencing either Nrf-2 or miR-146a led to increased neointima formation of injured rat carotid artery under physiological levels of flow. Overexpressing miR-146a inhibits neointima formation of rat or mouse carotid artery induced by injury or flow cessation.

Conclusions

Nrf-2-mediated miR-146a expression is augmented by atheroprotective shear stress in ECs adjacent to sSMCs to inhibit neointima formation of injured arteries.

Atmospheric, oceanic, and subglacial forcing scenarios from the Sea-level Response to Ice Sheet Evolution (SeaRISE) project are applied to six three-dimensional thermomechanical ice-sheet models to assess Antarctic ice sheet sensitivity over a 500 year timescale and to inform future modeling and field studies. Results indicate (i) growth with warming, except within low-latitude basins (where inland thickening is outpaced by marginal thinning); (ii) mass loss with enhanced sliding (with basins dominated by high driving stresses affected more than basins with low-surface-slope streaming ice); and (iii) mass loss with enhanced ice shelf melting (with changes in West Antarctica dominating the signal due to its marine setting and extensive ice shelves; cf. minimal impact in the Terre Adelie, George V, Oates, and Victoria Land region of East Antarctica). Ice loss due to dynamic changes associated with enhanced sliding and/or sub-shelf melting exceeds the gain due to increased precipitation. Furthermore, differences in results between and within basins as well as the controlling impact of sub-shelf melting on ice dynamics highlight the need for improved understanding of basal conditions, grounding-zone processes, ocean-ice interactions, and the numerical representation of all three. Key Points Sensitivity study of Antarctica to atmospheric, oceanic and subglacial forcings Different sectors of Antarctica are vulnerable to the forcings Atmospheric forcing lead to a growth, but dynamic forcing lead to a mass loss ©2013. American Geophysical Union. All Rights Reserved.

The Sea-level Response to Ice Sheet Evolution (SeaRISE) effort explores the sensitivity of the current generation of ice sheet models to external forcing to gain insight into the potential future contribution to sea level from the Greenland and Antarctic ice sheets. All participating models simulated the ice sheet response to three types of external forcings: a change in oceanic condition, a warmer atmospheric environment, and enhanced basal lubrication. Here an analysis of the spatial response of the Greenland ice sheet is presented, and the impact of model physics and spin-up on the projections is explored. Although the modeled responses are not always homogeneous, consistent spatial trends emerge from the ensemble analysis, indicating distinct vulnerabilities of the Greenland ice sheet. There are clear response patterns associated with each forcing, and a similar mass loss at the full ice sheet scale will result in different mass losses at the regional scale, as well as distinct thickness changes over the ice sheet. All forcings lead to an increased mass loss for the coming centuries, with increased basal lubrication and warmer ocean conditions affecting mainly outlet glaciers, while the impacts of atmospheric forcings affect the whole ice sheet. Key Points Sensitivity study of Greenland to atmospheric, oceanic and subglacial forcings Each forcing result in a different regional thickness response All forcings lead to an increased mass loss for the coming centuries ©2013. American Geophysical Union. All Rights Reserved.