Potentiation of macrophage Piezo1 by atherogenic 7-ketocholesterol

Abstract

The mechanosensitive ion channel Piezo1 present in endothelial and smooth muscle cells, as well as in macrophages, is emerging as a novel, important player in the etiology of atherosclerosis. Here, we show that myeloid-specific deficiency of Piezo1 in atherogenic Ldlr^-/- mice reduces plaque formation. Moreover, chronic oxLDL, as well as its main oxysterol 7-ketocholesterol (7-KC), promotes Piezo1 opening by pressure stimulation in both mouse macrophages and transfected HEK cells. 7-KC dramatically enhances Piezo1 current amplitude and slows down inactivation and deactivation. This up-modulation involves an increase in Piezo1 expression, as well as a potentiation of mechanical gating that depends on membrane cholesterol depletion and decreased order. By contrast, Piezo1 is inhibited by the athero-protective free docosahexaenoic acid, either without or with 7-KC. Altogether, these findings indicate that macrophage Piezo1 is differentially modulated by pro- and anti-atherogenic lipids, pointing to the role of Piezo1 and its potentiation by oxysterols in atherosclerosis.

Keywords: 7-ketocholesterol; CP: Cell biology; CP: Metabolism; PUFAs; atherosclerosis; cholesterol; docosahexaenoic acid; ion channels; macrophage; mechanobiology; oxLDL; patch clamp.