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Cardiovasc Res. 2020 Mar 14. pii: cvaa067. doi: 10.1093/cvr/cvaa067. [Epub ahead of print]

Sectm1a Deficiency Aggravates Inflammation-Triggered Cardiac Dysfunction through Disruption of LXRα Signaling in Macrophages.

Author information

1
Pharmacology and Systems Physiology, University of Cincinnati College of Medicine.
2
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
3
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine.
4
Department of Pediatrics, University of Cincinnati College of Medicine.
5
Division of Biomedical Informatics, Cincinnati Children's Hospital, Cincinnati, OH, USA.
6
Internal Medicine, University of Cincinnati College of Medicine.
7
Critical Illness Research, Lawson Health Research Institute, Ontario N6A 4G5, Canada.
8
Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine.

Abstract

AIM:

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 LPS injection, when compared to 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 downregulated 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 signaling in macrophages. Our data suggest that augmenting Sectm1a activity may be a potential therapeutic approach to resolve inflammation and associated cardiac dysfunction.

TRANSLATIONAL PERSPECTIVE:

Better understanding on the interaction between inflammatory responses and cardiac health is prominent for the development of safer and more efficacious therapies for heart failure patients. The present study, using both acute (LPS) and chronic (high-fat diet) inflammation models, reiterated the adverse effects of abnormal macrophages activation on cardiac function. Our Sectm1a knockout mouse model showed exacerbated cardiac and systemic inflammatory responses, resulting in further aggravation of contractile dysfunction on the heart after endotoxin challenge. We also demonstrated Sectm1a as a new regulator of macrophage function through LXRα pathway. These data suggest a novel approach to regulate macrophage-elicited inflammation.

PMID:
32170929
DOI:
10.1093/cvr/cvaa067

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