In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. Suppl_3 ( 2020-11-17)
Abstract:
Objective: Pulmonary arterial hypertension (PAH) is a lung disease characterized by vascular lesions and obstruction of distal pulmonary arteries (PA) leading to right ventricle (RV) remodeling and death. Similar to cancer cells, PA smooth muscle cells (PASMCs) exhibit an excessive proliferation and resistance to apoptosis, pivot components of vascular remodeling, due to epigenetic reprogramming and Warburg effect. This epigenetic/metabolic signature is attributed in part to the upregulation of ATP citrate lyase (ACLY). By decreasing cytosolic levels of citrate, ACLY supports glycolysis, while by generating acetyl-coA in the nucleus it promotes histone acetylation and signaling pathways supporting pathological processes like proliferation, hypertrophy, and fibrosis, pathological features in PAH. In the cytosol, ACLY controls the synthesis of lipids required for proliferating cells to generate membranes. We thus hypothesized that ACLY is upregulated in PAH and contributes to PA remodeling and RV failure. Methods/Results: Using immunoblot, we showed an upregulation of ACLY in human distal PA and isolated PASMCs from PAH patients (p 〈 0.05 ; n=10), like in Sugen/Hypoxia rat model. In vitro, pharmacological inhibition of ACLY significantly decreased PAH-PASMC proliferation (Ki67 labeling), resistance to apoptosis (Annexin V and caspase 3 assays) and restored a proper metabolism (seahorse assay) (p 〈 0.05 ; n=5). Mechanistically, we showed that ACLY inhibition decreases P300-dependent pro-survival factors including Survivin, PCNA, cMYC, PKM2, phospho-PDH / PDH, and restores FOXO3 and AMPK functions know to be decreased in PAH. Besides, we found that ACLY expression was upregulated in failed RV from rats subjected to pulmonary artery banding; its expression correlating negatively with stroke volume and positively with RVEDP; hypertrophy and fibrosis. Conclusion: Our preliminary data suggest that ACLY contributes to vascular remodeling in PAH. Current experiments aim to demonstrate whether 1) pharmacological inhibition of ACLY reverses PAH in animal models and 2) whether inactivation of Acly targeted to smooth muscle cells and cardiomyocytes improves pulmonary vascular remodeling and RV dysfunction, respectively.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.142.suppl_3.15608
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2020
detail.hit.zdb_id:
1466401-X
