Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA.
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
Cardiovasc Res. 2021 Feb 22;117(3):890-902. doi: 10.1093/cvr/cvaa067.
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.
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.
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.
心脏功能障碍是炎症稳态失调的常见合并症，这种失调在败血症（急性）或肥胖症（慢性）等情况下很常见。跨膜蛋白 1a（Sectm1a）先前被认为可以调节炎症反应，但它在与炎症相关的心脏功能障碍中的作用几乎未知。
我们使用 CRISPR/Cas9 系统生成了全身性 Sectm1a 敲除（KO）小鼠模型，并观察到与野生型（WT）对照组相比，经脂多糖（LPS）注射后 KO 小鼠的死亡率和心脏损伤显著增加。进一步的分析显示，LPS 处理后的 KO 小鼠心脏中炎症性巨噬细胞的积累明显增加。因此，Sectm1a 的缺失显著增加了 LPS 刺激后体外（来自骨髓来源的巨噬细胞（BMDMs））和体内（血清和心肌）炎症细胞因子的水平。RNA 测序结果和生物信息学分析表明，KO-BMDMs 中最显著下调的基因受到 LXRα的调节，LXRα 是巨噬细胞中具有强大抗炎活性的核受体。事实上，我们发现，用 GW3965（LXR 激动剂）处理时，KO-BMDMs 中的 LXRα 核易位被破坏，导致炎症细胞因子水平升高，与 GW3965 处理的 WT 细胞相比。此外，在高脂肪饮食（HFD）喂养的慢性炎症模型中，我们观察到 KO 心脏中炎症性单核细胞/巨噬细胞的浸润大大增加，相应地，心脏功能恶化，与 WT-HFD 对照组相比。
本研究通过调节巨噬细胞中的 LXRα 信号通路，将 Sectm1a 定义为一种新的炎症诱导性心脏功能障碍的调节因子。我们的数据表明，增强 Sectm1a 的活性可能是解决炎症和相关心脏功能障碍的一种潜在治疗方法。
