Abstract 13184: ATP Citrate Lyase a New Therapeutic Target for Vascular Remodeling Diseases
| Autor: | Yann Grobs, Sarah-eve Lemay, Charlotte Romanet, Sandra Breuils Bonnet, Mark Orcholski, Alice Bourgeois, Melanie Sauvaget, Kana Shimauchi, Pierre Voisine, Roxane Paulin, Francois Potus, Steeve Provencher, Olivier BOUCHERAT, Sebastien Bonnet |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Circulation. 144 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | 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 (pIn 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 (pin 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) (pIn 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. |
| Databáze: | OpenAIRE |
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