PHLPP1 inhibition in vascular smooth muscle cells alleviates atherosclerotic plaque formation via up-regulating autophagy in ApoE−/− mice

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Abstract PH domain and leucine-rich repeat protein phosphatase1 (PHLPP1) is a recently identified serine/threonine protein phosphatase which plays a critical role in metabolic disorders through dephosphorylation of its downstream targets, but the association between PHLPP1 and atherosclerosis as well as vascular smooth muscle cell (VSMC)-derived foam cell formation remains poorly understood. This study investigates the function and mechanisms of PHLPP1 inhibition in atherosclerotic plaque progression and VSMC-derived foam cell formation. In vivo, the expression of PHLPP1 in ApoE −/− mice was knocked down by lentivirus-mediated short hairpin RNA (shRNA). HE staining, Oil Red O staining, immunohistochemistry and immunofluorescence of aortic sinus sections were performed. Similarly, in vitro, the expression of PHLPP1 was inhibited using PHLPP1-siRNA; and then the primary VSMCs were exposed to 80 µg/ml oxidized low-density lipoprotein (ox-LDL) for the following experiments. The expression of PHLPP1 was up-regulated in both atherosclerotic plaques and ox-LDL treated primary VSMCs. Furthermore, PHLPP1 inhibition ameliorated the atherosclerotic plaque formation in high-fat diet fed ApoE −/− mice (atherosclerosis model) independent of LDL-C levels. Additionally, PHLPP1 knockdown reduced the lipid accumulation and improved the autophagy level in VSMCs mediated by activating AMPK signaling pathway, which could be blocked by 3-MA (an autophagy inhibitor) and compound C (an AMPK inhibitor). Inhibition of PHLPP1 expression alleviates atherosclerotic plaque progression and ameliorates lipid deposition in VSMCs, an effect associated with enhanced autophagy mediated by increased AMPK phosphorylation in advanced atherosclerosis.

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