Bempedoic acid, an ATP citrate lyase inhibitor, reduces intimal hyperplasia via activation of AMPKα signaling pathway

Abstract

Background: One of the common pathophysiological basis of atherosclerosis is intimal hyperplasia. ATP citrate lyase (ACLY) has been reported as a promising therapeutic target for treatment of dyslipidemia and atherosclerosis. However, the role of ACLY in intimal hyperplasia has yet to be clarified.

Methods: The current investigation studies the molecular effects of ACLY and bempedoic acid, an ACLY inhibitor, on platelet-derived growth factor (PDGF)-induced primary human aortic smooth muscle cells (HASMCs) proliferation in vitro and on femoral arterial wire-injured neointimal hyperplasia in mouse in vivo. The role of ACLY in intimal hyperplasia was further investigated in mice treated with bempedoic acid. Cell proliferation was measured by CCK8 and BrdU assays. We explored further mechanisms using western blot, qPCR and immunofluorescence.

Results: We found that ACLY was significantly increased in dedifferentiated VSMC in vitro and vivo. Bempedoic acid which can inhibit ACLY expression effectively blocked PDGF-induced VSMC proliferation and dedifferentiation by activating AMPK/ACC signaling pathway. Moreover, bempedoic acid also attenuated VSMC proliferation and inhibited VSMC dedifferentiation in the wire-injured mouse femoral arteries, resulting in reduced neointima formation.

Conclusions: We demonstrates that bempedoic acid reduces ACLY expression to restrain VSMC proliferation and dedifferentiation by activating AMPK/ACC signaling pathway, which may provide a potential therapeutic strategy for diseases associated with intimal hyperplasia including restenosis and atherosclerosis.

Keywords: ACLY; AMPK; Bempedoic acid; Intimal hyperplasia; Vascular smooth muscle cell.