PMID- 37235928 OWN - NLM STAT- MEDLINE DCOM- 20230809 LR - 20231003 IS - 1095-8584 (Electronic) IS - 0022-2828 (Print) IS - 0022-2828 (Linking) VI - 181 DP - 2023 Aug TI - Suppression of myeloid YAP antagonizes adverse cardiac remodeling during pressure overload stress. PG - 1-14 LID - S0022-2828(23)00090-1 [pii] LID - 10.1016/j.yjmcc.2023.05.004 [doi] AB - Inflammation is an integral component of cardiovascular disease and is thought to contribute to cardiac dysfunction and heart failure. While ischemia-induced inflammation has been extensively studied in the heart, relatively less is known regarding cardiac inflammation during non-ischemic stress. Recent work has implicated a role for Yes-associated protein (YAP) in modulating inflammation in response to ischemic injury; however, whether YAP influences inflammation in the heart during non-ischemic stress is not described. We hypothesized that YAP mediates a pro-inflammatory response during pressure overload (PO)-induced non-ischemic injury, and that targeted YAP inhibition in the myeloid compartment is cardioprotective. In mice, PO elicited myeloid YAP activation, and myeloid-specific YAP knockout mice (YAP(F/F);LysM(Cre)) subjected to PO stress had better systolic function, and attenuated pathological remodeling compared to control mice. Inflammatory indicators were also significantly attenuated, while pro-resolving genes including Vegfa were enhanced, in the myocardium, and in isolated macrophages, of myeloid YAP KO mice after PO. Experiments using bone marrow-derived macrophages (BMDMs) from YAP KO and control mice demonstrated that YAP suppression shifted polarization toward a resolving phenotype. We also observed attenuated NLRP3 inflammasome priming and function in YAP deficient BMDMs, as well as in myeloid YAP KO hearts following PO, indicating disruption of inflammasome induction. Finally, we leveraged nanoparticle-mediated delivery of the YAP inhibitor verteporfin and observed attenuated PO-induced pathological remodeling compared to DMSO nanoparticle control treatment. These data implicate myeloid YAP as an important molecular nodal point that facilitates cardiac inflammation and fibrosis during PO stress and suggest that selective inhibition of YAP may prove a novel therapeutic target in non-ischemic heart disease. CI - Copyright (c) 2023 Elsevier Ltd. All rights reserved. FAU - Francisco, Jamie AU - Francisco J AD - Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA. FAU - Guan, Jin AU - Guan J AD - Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA. FAU - Zhang, Yu AU - Zhang Y AD - Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA. FAU - Nakada, Yasuki AU - Nakada Y AD - Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA. FAU - Mareedu, Satvik AU - Mareedu S AD - Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA. FAU - Sung, Eun-Ah AU - Sung EA AD - Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA. FAU - Hu, Che-Ming AU - Hu CM AD - Institute of Biomedical Sciences, Academia Sinica, Taiwan. FAU - Oka, Shinichi AU - Oka S AD - Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA. FAU - Zhai, Peiyong AU - Zhai P AD - Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA. FAU - Sadoshima, Junichi AU - Sadoshima J AD - Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA. FAU - Del Re, Dominic P AU - Del Re DP AD - Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA. Electronic address: delredo@njms.rutgers.edu. LA - eng GR - F31 HL162545/HL/NHLBI NIH HHS/United States GR - R01 HL127339/HL/NHLBI NIH HHS/United States GR - R01 HL157483/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230524 PL - England TA - J Mol Cell Cardiol JT - Journal of molecular and cellular cardiology JID - 0262322 RN - 0 (Inflammasomes) SB - IM MH - Mice MH - Animals MH - *Inflammasomes/metabolism MH - *Ventricular Remodeling MH - Heart MH - Myocardium/metabolism MH - Inflammation/pathology MH - Mice, Knockout MH - Mice, Inbred C57BL PMC - PMC10524516 MID - NIHMS1904101 OTO - NOTNLM OT - Fibrosis OT - Heart failure OT - Inflammation OT - Macrophage OT - Pressure overload COIS- Declaration of Competing Interest Nothing to disclose. EDAT- 2023/05/27 09:42 MHDA- 2023/08/09 06:43 PMCR- 2024/08/01 CRDT- 2023/05/26 18:02 PHST- 2023/02/27 00:00 [received] PHST- 2023/05/05 00:00 [revised] PHST- 2023/05/16 00:00 [accepted] PHST- 2024/08/01 00:00 [pmc-release] PHST- 2023/08/09 06:43 [medline] PHST- 2023/05/27 09:42 [pubmed] PHST- 2023/05/26 18:02 [entrez] AID - S0022-2828(23)00090-1 [pii] AID - 10.1016/j.yjmcc.2023.05.004 [doi] PST - ppublish SO - J Mol Cell Cardiol. 2023 Aug;181:1-14. doi: 10.1016/j.yjmcc.2023.05.004. Epub 2023 May 24.