An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis.

Autor:	Abe JI; Departments of Cardiology (J.-i.A., M.I., K.A.K., V.S.K.S., L.-L.L., A.P.B., Y.J.G., A.D., N.L.P., K.F., S. Kotla), The University of Texas MD Anderson Cancer Center, Houston, TX., Imanishi M; Departments of Cardiology (J.-i.A., M.I., K.A.K., V.S.K.S., L.-L.L., A.P.B., Y.J.G., A.D., N.L.P., K.F., S. Kotla), The University of Texas MD Anderson Cancer Center, Houston, TX., Li S; Department of Cardiovascular Sciences (S.L., T.-H.-M.N., R.J.A., E.A.O.-D., J.P.C., G.W., N.-T.L.), Houston Methodist Research Institute, Houston, TX., Zhang A; Center for Bioenergetics (A.Z., A.A.G., H.J.P., D.J.H.), Houston Methodist Research Institute, Houston, TX.; Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, Houston, TX (A.Z., A.A.G., H.J.P., D.J.H.)., Ko KA; Departments of Cardiology (J.-i.A., M.I., K.A.K., V.S.K.S., L.-L.L., A.P.B., Y.J.G., A.D., N.L.P., K.F., S. Kotla), The University of Texas MD Anderson Cancer Center, Houston, TX., Samanthapudi VSK; Departments of Cardiology (J.-i.A., M.I., K.A.K., V.S.K.S., L.-L.L., A.P.B., Y.J.G., A.D., N.L.P., K.F., S. Kotla), The University of Texas MD Anderson Cancer Center, Houston, TX., Lee LL; Departments of Cardiology (J.-i.A., M.I., K.A.K., V.S.K.S., L.-L.L., A.P.B., Y.J.G., A.D., N.L.P., K.F., S. Kotla), The University of Texas MD Anderson Cancer Center, Houston, TX., Bojorges AP; Departments of Cardiology (J.-i.A., M.I., K.A.K., V.S.K.S., L.-L.L., A.P.B., Y.J.G., A.D., N.L.P., K.F., S. Kotla), The University of Texas MD Anderson Cancer Center, Houston, TX., Gi YJ; Departments of Cardiology (J.-i.A., M.I., K.A.K., V.S.K.S., L.-L.L., A.P.B., Y.J.G., A.D., N.L.P., K.F., S. Kotla), The University of Texas MD Anderson Cancer Center, Houston, TX., Hobbs BP; Department of Population Health, The University of Texas at Austin, Austin, TX (B.P.H.)., Deswal A; Departments of Cardiology (J.-i.A., M.I., K.A.K., V.S.K.S., L.-L.L., A.P.B., Y.J.G., A.D., N.L.P., K.F., S. Kotla), The University of Texas MD Anderson Cancer Center, Houston, TX., Herrmann J; Cardio Oncology Clinic, Division of Preventive Cardiology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (J.H.)., Lin SH; Radiation Oncology (S.H.L.), The University of Texas MD Anderson Cancer Center, Houston, TX., Chini EN; Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL (E.N.C.)., Shen YH; Division of Cardiothoracic Surgery, Baylor College of Medicine, Houston, TX (Y.H.S.)., Schadler KL; Pediatric Research (K.L.S.), The University of Texas MD Anderson Cancer Center, Houston, TX., Nguyen TH; Department of Cardiovascular Sciences (S.L., T.-H.-M.N., R.J.A., E.A.O.-D., J.P.C., G.W., N.-T.L.), Houston Methodist Research Institute, Houston, TX., Gupte AA; Center for Bioenergetics (A.Z., A.A.G., H.J.P., D.J.H.), Houston Methodist Research Institute, Houston, TX.; Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, Houston, TX (A.Z., A.A.G., H.J.P., D.J.H.)., Reyes-Gibby C; Emergency Medicine (C.R.-G., S.-C.J.Y.), The University of Texas MD Anderson Cancer Center, Houston, TX., Yeung SJ; Emergency Medicine (C.R.-G., S.-C.J.Y.), The University of Texas MD Anderson Cancer Center, Houston, TX., Abe RJ; Department of Cardiovascular Sciences (S.L., T.-H.-M.N., R.J.A., E.A.O.-D., J.P.C., G.W., N.-T.L.), Houston Methodist Research Institute, Houston, TX., Olmsted-Davis EA; Department of Cardiovascular Sciences (S.L., T.-H.-M.N., R.J.A., E.A.O.-D., J.P.C., G.W., N.-T.L.), Houston Methodist Research Institute, Houston, TX., Krishnan S; Department of Neurosurgery (S. Krishnan), The University of Texas Health Science Center at Houston, Houston, TX., Dantzer R; Symptom Research (R.D.), The University of Texas MD Anderson Cancer Center, Houston, TX., Palaskas NL; Departments of Cardiology (J.-i.A., M.I., K.A.K., V.S.K.S., L.-L.L., A.P.B., Y.J.G., A.D., N.L.P., K.F., S. Kotla), The University of Texas MD Anderson Cancer Center, Houston, TX., Cooke JP; Department of Cardiovascular Sciences (S.L., T.-H.-M.N., R.J.A., E.A.O.-D., J.P.C., G.W., N.-T.L.), Houston Methodist Research Institute, Houston, TX., Pownall HJ; Center for Bioenergetics (A.Z., A.A.G., H.J.P., D.J.H.), Houston Methodist Research Institute, Houston, TX.; Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, Houston, TX (A.Z., A.A.G., H.J.P., D.J.H.)., Yoshimoto M; Center for Stem Cell and Regenerative Medicine, Institute of Molecular Medicine (M.Y.), The University of Texas Health Science Center at Houston, Houston, TX., Fujiwara K; Departments of Cardiology (J.-i.A., M.I., K.A.K., V.S.K.S., L.-L.L., A.P.B., Y.J.G., A.D., N.L.P., K.F., S. Kotla), The University of Texas MD Anderson Cancer Center, Houston, TX., Hamilton DJ; Center for Bioenergetics (A.Z., A.A.G., H.J.P., D.J.H.), Houston Methodist Research Institute, Houston, TX.; Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, Houston, TX (A.Z., A.A.G., H.J.P., D.J.H.)., Burks JK; Leukemia, Division of Cancer Medicine (J.K.B.), The University of Texas MD Anderson Cancer Center, Houston, TX., Wang G; Department of Cardiovascular Sciences (S.L., T.-H.-M.N., R.J.A., E.A.O.-D., J.P.C., G.W., N.-T.L.), Houston Methodist Research Institute, Houston, TX., Le NT; Department of Cardiovascular Sciences (S.L., T.-H.-M.N., R.J.A., E.A.O.-D., J.P.C., G.W., N.-T.L.), Houston Methodist Research Institute, Houston, TX., Kotla S; Departments of Cardiology (J.-i.A., M.I., K.A.K., V.S.K.S., L.-L.L., A.P.B., Y.J.G., A.D., N.L.P., K.F., S. Kotla), The University of Texas MD Anderson Cancer Center, Houston, TX.
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2023 Jun 23; Vol. 133 (1), pp. 25-44. Date of Electronic Publication: 2023 Jun 02.
DOI:	10.1161/CIRCRESAHA.122.322017
Abstrakt:	Background: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis. Methods: A ERK5 S496A (dephosphorylation mimic) knock in (KI) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and wild type (WT) mice was studied using imaging mass cytometry. Bone marrow-derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis. Results: We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow-derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)-induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors. Conclusions: We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation. Competing Interests: Disclosures S.H. Lin is an Advisory Board member of AstraZeneca, Beyond Spring Pharmaceuticals, and STCube Pharmaceuticals. The other authors report no conflicts.
Databáze:	MEDLINE
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