Yutian Li1, Shan Deng2, Xiaohong Wang1, Wei Huang3, Jing Chen4,5, Nathan Robbins6, Xingjiang Mu1, Kobina Essandoh1, Tianqing Peng7, Anil G Jegga4, Jack Rubinstein6, David E Adams8, Yigang Wang3, Jiangtong Peng2, Guo-Chang Fan1. 1. Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. 2. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China. 3. Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. 4. Division of Biomedical Informatics, Cincinnati Children's Hospital, Cincinnati, OH 45267, USA. 5. Department of Pediatrics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. 6. Department of Internal Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. 7. Critical Illness Research, Lawson Health Research Institute, London, ON N6A 4G5, Canada. 8. Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA.
Abstract
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 LXRα, a nuclear receptor with robust anti-inflammatory activity in macrophages. Indeed, we identified that the nuclear translocation of LXRα 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 LXRα signalling in macrophages. Our data suggest that augmenting Sectm1a activity may be a potential therapeutic approach to resolve inflammation and associated cardiac dysfunction. Published on behalf of the European Society of Cardiology. All rights reserved.
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 LXRα, a nuclear receptor with robust anti-inflammatory activity in macrophages. Indeed, we identified that the nuclear translocation of LXRα 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 LXRα signalling in macrophages. Our data suggest that augmenting Sectm1a activity may be a potential therapeutic approach to resolve inflammation and associated cardiac dysfunction. Published on behalf of the European Society of Cardiology. All rights reserved.
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