Targeting Piezo1 mechanotransduction in myeloid cells against atherosclerosis – Piezo1-Athero

Atherosclerosis (AS) is a common chronic inflammatory vascular disease characterized by the formation of fatty plaques within the arterial wall that narrow the lumen, with a further risk of plaque rupture and thrombosis. Macrophages (M?) contribute to the initiation and progression of AS by engulfing oxidized LDL (oxLDL), converting into foam cells and forming a fatty streak. Typically, plaques form at sites of disturbed blood flow, such as arterial curvatures and bifurcations. The mechanosensitive (MS) ion channel Piezo1 present in M? is emerging as a novel important player in the etiology of AS. Our preliminary findings indicate that chronic oxLDL, as well as its major oxysterol 7-ketocholesterol (7-KC), cause a potentiation of Piezo1 to mechanical stimulation in both mouse M??and transfected HEK cells. 7-KC induces an increase in Piezo1 current amplitude, as well as a slowing down of channel inactivation. In vivo, we analyzed the cellular composition of AS aortas from Western diet-fed hypercholesterolemic Ldlr-/- mice, which received WT or Piezo1 KO (Lysm Cre Piezo1del/fl TomatoSTOPfl) bone marrow transplants. While complete blood count was similar between both groups, the number of Tomato positive myeloid cells is reduced by about 50% in the aortas of mice complemented with KO transplants versus WT, with an even stronger reduction in the number of M?. Moreover, atheromatous plaque formation is significantly reduced in the KO. Altogether, our initial findings indicate that M? Piezo1 is up-modulated by pro-atherogenic lipids and plays an important role in AS progression. Our specific aims in this project are to: 1) investigate Piezo1 function in monocytes (Mono) and M? foam cells; 2) decipher how Piezo1 influences Mono aortic infiltration and/or M? egress; 3) explore the potential role of Piezo1 in aortic M? differentiation; 4) target M??Piezo1 in AS using a dietary strategy. Globally, we will provide novel knowledge concerning the role of Piezo1 in innate immunity and its implication in AS progression.