Simvastatin inhibits POVPC-mediated induction of endothelial-to-mesenchymal cell transition

Abstract

Endothelial-to-mesenchymal transition (EndMT), the process by which an endothelial cell (EC) undergoes a series of molecular events that result in a mesenchymal cell phenotype, plays an important role in atherosclerosis. 1-Palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), derived from the oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine, is a proinflammatory lipid found in atherosclerotic lesions. Whether POVPC promotes EndMT and how simvastatin influences POVPC-mediated EndMT remains unclear. Here, we treated human umbilical vein ECs with POVPC, simvastatin, or both, and determined their effect on EC viability, morphology, tube formation, proliferation, and generation of NO and superoxide anion (O 2 •− ). Expression of specific endothelial and mesenchymal markers was detected by immunofluorescence and immunoblotting. POVPC did not affect EC viability but altered cellular morphology from cobblestone-like ECs to a spindle-like mesenchymal cell morphology. POVPC increased O 2 − generation and expression of alpha-smooth muscle actin, vimentin, Snail-1, Twist-1, transforming growth factor-beta (TGF-β), TGF-β receptor II, p-Smad2/3, and Smad2/3. POVPC also decreased NO production and expression of CD31 and endothelial NO synthase. Simvastatin inhibited POVPC-mediated effects on cellular morphology, production of O 2 •− and NO, and expression of specific endothelial and mesenchymal markers. These data demonstrate that POVPC induces EndMT by increasing oxidative stress, which stimulates TGF-β/Smad signaling, leading to Snail-1 and Twist-1 activation. Simvastatin inhibited POVPC-induced EndMT by decreasing oxidative stress, suppressing TGF-β/Smad signaling, and inactivating Snail-1 and Twist-1. Our findings reveal a novel mechanism of atherosclerosis that can be inhibited by simvastatin.

Endothelial to Mesenchymal Transition: An Insight in Atherosclerosis

“…A study by (25) has shown that simvastatin can inhibit EndMT via upregulation of KLF4/miR-483 axis in HUVECs. Additionally, simvastatin attenuated 1-Palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVC) inducing EndMT, by suppressing oxidative stress and TGF-β/SMAD signaling, suggesting that simvastatin could potentially be used in treating atherosclerosis (97). Altogether, these findings suggest the therapeutic potential of EndMT disruption in atherosclerosis.…”

Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment

“…Indeed, previous work has linked EndMT to neointimal hyperplasia ( Chen et al, 2015 ; Moonen et al, 2015 ), increased leukocyte migration ( Evrard et al, 2016 ), lipid uptake by lesional macrophages ( Chen et al, 2019 ), and oxidative stress ( Evrard et al, 2016 ) in the developing plaque ( Figure 1 ). Moreover, statin therapy ( Li Y. et al, 2021 ), histone deacetylase inhibitors ( Chen et al, 2021 ), and microRNA inhibition ( Wu et al, 2021 ) have recently been investigated as potential strategies for limiting EndMT, the latter of which was observed to reduce plaque formation in atherosclerotic mice.…”

The Levels of Oxidized Phospholipids in High-Density Lipoprotein During the Course of Sepsis and Their Prognostic Value

“…It has been shown the truncated Ox-PAPCs, including POVPC and PGPC, can induce vascular leaking and exacerbate inflammation, due to their direct pro-inflammatory effects on both endothelial cell and macrophages ( 24 , 34 , 35 ). The deleterious effects of POVPC on endothelial function have been highlighted for decades in cardiovascular diseases ( 36 – 38 ). Therefore, the variety of POVPC function could be an explanation for why HDL POVPC was not significantly correlated with these SOFA scores, plasma CRP, and other pro-inflammatory cytokines enhanced in septic patients.…”