Laminar flow inhibits the Hippo/YAP pathway via autophagy and SIRT1-mediated deacetylation against atherosclerosis

Abstract

Atherosclerosis is a multifactorial disease of the vasculature, and shear stress is a crucial regulator of its process. Disturbed flow promotes atherosclerotic effects, while laminar flow has a protective action on the endothelium. Hippo/YAP is a major cascade that senses various mechanical cues and mediates the expression of pro-inflammatory genes. However, the mechanism modulating the transcription factor YAP in response to different patterns of blood flow remains unclear. In this study, we provide evidence that shear stress modulates YAP activity via autophagy in endothelial cells. Laminar flow promoted the expression of the autophagic markers BECLIN 1 and LC3II/LC3I. Autophagy blockade using a chemical inhibitor repressed YAP degradation under laminar flow. Conversely, the induction of autophagy under disturbed flow partially antagonized the nuclear import and transcriptional activation of YAP. In parallel, laminar flow led to the increased expression of SIRT1 protein, a NAD +-dependent deacetylase. Further investigation showed that SIRT1-mediated YAP deacetylation. The forced expression of SIRT1 under disturbed flow effectively attenuated YAP activation and nuclear accumulation, thereby downregulating the expression of proinflammatory genes. In atheroprone vessels of mice receiving rapamycin to induce autophagy, the enhanced expression of SIRT1 was observed together with YAP repression. Altogether, these results show that endothelial autophagy and SIRT1 expression induced by laminar flow contribute to the inhibition of Hippo/YAP signaling and interrupt atherosclerotic plaque formation.

Emerging role of the Hippo pathway in autophagy

“… Shi et al 140 DCM Streptozotocin constructed diabetic model in endothelium-specific MST1 Tg mice CMEC/cardiomyocyte The MST1-enriched exosomes released from CMECs inhibit autophagy and glucose metabolism, thereby promote apoptosis in cardiomyocyte. Yuan et al 141 Atherosclerosis ApoE −/− mice HUVECs Laminar flow protects the endothelium, inhibits Hippo-YAP signaling by promoting endothelial autophagy and SIRT1 expression, and blocks the formation of atherosclerotic plaques. Wang et al 142 Atherosclerosis ApoE −/− : Mst1 −/− and ApoE −/− : Mst1 Tg mice Murine macrophage In ApoE ( −/− ) mice, MST1 may stabilize atherosclerotic plaques by inhibiting macrophage autophagy and promoting macrophage apoptosis.…”

KRAS K104 modification affects the KRASG12D-GEF interaction and mediates cell growth and motility

“…For immunoprecipitation experiments, 2 mg of cell lysate was incubated with specific antibodies and immobilized on protein A/G PLUS-agarose beads (Santa Cruz Biotechnology). Proteins were separated by SDS-PAGE, transferred to a nitrocellulose membrane and blotted with specific antibodies, including those against RAS (1:300, Thermo Fisher Scientific, #16117) 25 , GEF H1 (1:500, Abcam, ab155785) 26 , RASA1 (1:500, Abcam, ab2922) 27 , Ac-lysine (1:500, Abcam, ab21623) 28,29 , phospho-AKT (Ser-473, 1:500, Cell Signaling, #4051) 30 , AKT (1:500, Cell Signaling, #2920) 31 and β-actin (1;1000, Thermo Fisher Scientific, #AM4302) 32 , for western blotting.…”

Shear Stress and Metabolic Disorders—Two Sides of the Same Plaque

“…Kheloufi et al further revealed that high shear force boosts autophagy in ECs, and endothelial autophagy inhibits EC apoptosis, aging, and inflammation, collectively suppressing the formation of atherosclerotic plaques (81). The latest study demonstrates that LF induces YAP nuclear export mediated by SIRT1-dependent deacetylation and degradation through autophagy, and subsequently inhibits atherogenesis (193).…”