PMID- 32170929 OWN - NLM STAT- MEDLINE DCOM- 20220104 LR - 20240226 IS - 1755-3245 (Electronic) IS - 0008-6363 (Print) IS - 0008-6363 (Linking) VI - 117 IP - 3 DP - 2021 Feb 22 TI - Sectm1a deficiency aggravates inflammation-triggered cardiac dysfunction through disruption of LXRalpha signalling in macrophages. PG - 890-902 LID - 10.1093/cvr/cvaa067 [doi] AB - AIMS: Cardiac dysfunction is a prevalent comorbidity of disrupted inflammatory homeostasis observed in conditions such as sepsis (acute) or obesity (chronic). Secreted and transmembrane protein 1a (Sectm1a) has previously been implicated to regulate inflammatory responses, yet its role in inflammation-associated cardiac dysfunction is virtually unknown. METHODS AND RESULTS: Using the CRISPR/Cas9 system, we generated a global Sectm1a-knockout (KO) mouse model and observed significantly increased mortality and cardiac injury after lipopolysaccharide (LPS) injection, when compared with wild-type (WT) control. Further analysis revealed significantly increased accumulation of inflammatory macrophages in hearts of LPS-treated KO mice. Accordingly, ablation of Sectm1a remarkably increased inflammatory cytokines levels both in vitro [from bone marrow-derived macrophages (BMDMs)] and in vivo (in serum and myocardium) after LPS challenge. RNA-sequencing results and bioinformatics analyses showed that the most significantly down-regulated genes in KO-BMDMs were modulated by LXRalpha, a nuclear receptor with robust anti-inflammatory activity in macrophages. Indeed, we identified that the nuclear translocation of LXRalpha was disrupted in KO-BMDMs when treated with GW3965 (LXR agonist), resulting in higher levels of inflammatory cytokines, compared to GW3965-treated WT-cells. Furthermore, using chronic inflammation model of high-fat diet (HFD) feeding, we observed that infiltration of inflammatory monocytes/macrophages into KO-hearts were greatly increased and accordingly, worsened cardiac function, compared to WT-HFD controls. CONCLUSION: This study defines Sectm1a as a new regulator of inflammatory-induced cardiac dysfunction through modulation of LXRalpha signalling in macrophages. Our data suggest that augmenting Sectm1a activity may be a potential therapeutic approach to resolve inflammation and associated cardiac dysfunction. CI - Published on behalf of the European Society of Cardiology. All rights reserved. (c) The Author(s) 2020. For permissions, please email: journals.permissions@oup.com. FAU - Li, Yutian AU - Li Y AD - Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. FAU - Deng, Shan AU - Deng S AD - Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China. FAU - Wang, Xiaohong AU - Wang X AD - Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. FAU - Huang, Wei AU - Huang W AD - Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. FAU - Chen, Jing AU - Chen J AD - Division of Biomedical Informatics, Cincinnati Children's Hospital, Cincinnati, OH 45267, USA. AD - Department of Pediatrics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. FAU - Robbins, Nathan AU - Robbins N AD - Department of Internal Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. FAU - Mu, Xingjiang AU - Mu X AD - Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. FAU - Essandoh, Kobina AU - Essandoh K AD - Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. FAU - Peng, Tianqing AU - Peng T AD - Critical Illness Research, Lawson Health Research Institute, London, ON N6A 4G5, Canada. FAU - Jegga, Anil G AU - Jegga AG AD - Division of Biomedical Informatics, Cincinnati Children's Hospital, Cincinnati, OH 45267, USA. FAU - Rubinstein, Jack AU - Rubinstein J AD - Department of Internal Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. FAU - Adams, David E AU - Adams DE AD - Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. FAU - Wang, Yigang AU - Wang Y AD - Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. FAU - Peng, Jiangtong AU - Peng J AD - Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China. FAU - Fan, Guo-Chang AU - Fan GC AD - Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. LA - eng GR - R01 GM126061/GM/NIGMS NIH HHS/United States GR - R01 GM132149/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Cardiovasc Res JT - Cardiovascular research JID - 0077427 RN - 0 (Cytokines) RN - 0 (Inflammation Mediators) RN - 0 (Lipopolysaccharides) RN - 0 (Liver X Receptors) RN - 0 (Membrane Proteins) RN - 0 (Nr1h3 protein, mouse) RN - 0 (SECTM1A protein, mouse) SB - IM MH - Animals MH - Cytokines/genetics/metabolism MH - Diet, High-Fat MH - Disease Models, Animal MH - Gene Expression Regulation MH - Heart Diseases/etiology/genetics/*metabolism/physiopathology MH - Inflammation/etiology/genetics/*metabolism/physiopathology MH - Inflammation Mediators/metabolism MH - Lipopolysaccharides MH - Liver X Receptors/genetics/*metabolism MH - Macrophages/*metabolism MH - Male MH - Membrane Proteins/*deficiency/genetics MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Phenotype MH - RAW 264.7 Cells MH - Rats, Sprague-Dawley MH - Signal Transduction MH - *Ventricular Function, Left MH - Rats PMC - PMC8453795 OTO - NOTNLM OT - Cardiac function OT - Cardiac inflammation OT - Inflammation OT - LXR OT - Macrophage EDAT- 2020/03/15 06:00 MHDA- 2022/01/05 06:00 PMCR- 2020/03/14 CRDT- 2020/03/15 06:00 PHST- 2019/11/20 00:00 [received] PHST- 2020/02/17 00:00 [revised] PHST- 2020/03/12 00:00 [accepted] PHST- 2020/03/15 06:00 [pubmed] PHST- 2022/01/05 06:00 [medline] PHST- 2020/03/15 06:00 [entrez] PHST- 2020/03/14 00:00 [pmc-release] AID - 5805388 [pii] AID - cvaa067 [pii] AID - 10.1093/cvr/cvaa067 [doi] PST - ppublish SO - Cardiovasc Res. 2021 Feb 22;117(3):890-902. doi: 10.1093/cvr/cvaa067.