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- W4285331886 abstract "Vascular remodeling diseases (VRD) like coronary artery diseases or in-stent restenosis are characterized by proliferative and apoptosis-resistant vascular smooth muscle cells (VSMCs). As in cancer, proliferative VSMCs have increased Warburg effect leading to an impairment in the acetyl-coA homeostasis resulting in a profound epigenetic reprogramming sustaining their survival overtime. ATP citrate lyase (ACLY) is a key enzyme of the acetyl-coA and cholesterol metabolism involved in cell survival and resistance to apoptosis, in part by promoting the Warburg effect and histone acetylation. Surprisingly, its role in VRD remains unknown. We hypothesized that ACLY inhibition reverses VRD. Using immunofluorescence and western blot, we showed a significant (p<0.05) upregulation of ACLY in remodeled distal coronary arteries (n=5), stenosed saphenous vein (n=3) and remodeled radial arteries (n=5) isolated from patients with VRD compared to non VRD donors. In vitro , we found that PDGF/FGF2-stimulated human rings of mammary arteries, saphenous veins or cultured VSMCs isolated from coronary arteries exhibit increased expression as well as AKT-dependent activation and nuclear accumulation of ACLY (p<0.05). These effects were associated with a profound increase in cell proliferation (Ki67) and repression of apoptosis (Annexin V). Consistently, acetylation-dependent upregulation of the pro-proliferative markers PCNA, MCM2 and PLK1 (p<0.05) and the cell survival marker SURVIVIN was observed (p<0.05)). All these effects were dose-dependently inhibited by pharmacological inhibition of ACLY using BMS303141. Using a standard in vivo rat carotid injury model, we showed that the clinically available ACLY inhibitor ETC-1002 (n=10) prevents carotid remodeling 14 days post-injury compared to vehicle treated rats (n=10) (p<0.05). We demonstrated that ACLY upregulation in VRD is associated with vascular remodeling through increased smooth muscle cell proliferation and resistance to apoptosis. In vivo , ETC-1002 prevents remodeling in a rat carotid injury model. In vivo experiments using Acly smooth muscle cell-specific knockout mice are currently performed to further characterize the therapeutic potential of ACLY inhibition in VRD." @default.
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- W4285331886 date "2021-11-16" @default.
- W4285331886 modified "2023-09-23" @default.
- W4285331886 title "Abstract 13184: ATP Citrate Lyase a New Therapeutic Target for Vascular Remodeling Diseases" @default.
- W4285331886 doi "https://doi.org/10.1161/circ.144.suppl_1.13184" @default.
- W4285331886 hasPublicationYear "2021" @default.
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