Heme Oxygenase-1 in Macrophages Drives Septic Cardiac Dysfunction via Suppressing Lysosomal Degradation of Inducible Nitric Oxide Synthase
Heme Oxygenase-1 in Macrophages Drives Septic Cardiac Dysfunction via Suppressing Lysosomal Degradation of Inducible Nitric Oxide Synthase
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巨噬细胞中的血红素加氧酶-1 通过抑制诱导型一氧化氮合酶的溶酶体降解来驱动脓毒症性心脏功能障碍
DOI：
10.1161/circresaha.118.312910
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发表时间：
2018-05-25
影响因子：
20.1
通讯作者：
Xiang, Meixiang
中科院分区：
文献类型：
--
作者：
Jia, Liangliang;Wang, Yaping;Xiang, Meixiang
理由：迄今为止，我们对 HO-1（血红素加氧酶-1）在炎症性疾病中作用的理解主要局限于其催化功能及其血红素相关分解代谢产物抑制炎症和氧化应激的潜力。巨噬细胞中的 HO-1 是否以及如何在脓毒症心功能障碍的发展中发挥作用尚未被探索。目的：在这里，我们研究了巨噬细胞源性 HO-1 在脓毒症心功能障碍中的作用。方法和结果：腹腔注射脂多糖显着激活心脏浸润巨噬细胞中HO-1的表达。令人惊讶的是，我们发现小鼠骨髓条件性HO-1缺失在体内引起了对脂多糖引发的脓毒症心脏功能障碍和致死的抵抗，伴随着脓毒症心脏中心肌细胞凋亡的减少以及心脏浸润巨噬细胞中过氧亚硝酸盐的产生和iNOS（诱导型NO合酶）的减少，而促炎细胞因子的产生和巨噬细胞浸润没有改变。我们进一步证明，HO-1 抑制消除了脂多糖诱导的 iNOS 蛋白而不是巨噬细胞中 mRNA 的表达。此外，我们证实 HO-1 的抑制通过巨噬细胞中的溶酶体途径而不是蛋白酶体途径促进 iNOS 降解。巴弗洛霉素 A1 抑制 iNOS 的溶酶体降解会导致骨髓 HO-1 缺陷小鼠的败血症性心功能障碍。从机制上讲，我们证明 HO-1 在黄素单核苷酸结构域与 iNOS 相互作用，进一步阻止 iNOS 与 LC3（轻链 3）缀合以及随后在巨噬细胞中的溶酶体降解。这些影响与 HO-1 的分解代谢产物：亚铁离子、一氧化碳和胆红素无关。结论：我们的结果表明巨噬细胞中的 HO-1 会导致脓毒症心功能障碍。这些机制见解为治疗脓毒症心功能障碍提供了潜在的治疗靶点。
Rationale: To date, our understanding of the role of HO-1 (heme oxygenase-1) in inflammatory diseases has mostly been limited to its catalytic function and the potential for its heme-related catabolic products to suppress inflammation and oxidative stress. Whether and how HO-1 in macrophages plays a role in the development of septic cardiac dysfunction has never been explored. Objective: Here, we investigated the role of macrophage-derived HO-1 in septic cardiac dysfunction. Methods and Results: Intraperitoneal injection of lipopolysaccharide significantly activated HO-1 expression in cardiac infiltrated macrophages. Surprisingly, we found that myeloid conditional HO-1 deletion in mice evoked resistance to lipopolysaccharide-triggered septic cardiac dysfunction and lethality in vivo, which was accompanied by reduced cardiomyocyte apoptosis in the septic hearts and decreased peroxynitrite production and iNOS (inducible NO synthase) in the cardiac infiltrated macrophages, whereas proinflammatory cytokine production and macrophage infiltration were unaltered. We further demonstrated that HO-1 suppression abolished the lipopolysaccharide-induced iNOS protein rather than mRNA expression in macrophages. Moreover, we confirmed that the inhibition of HO-1 promoted iNOS degradation through a lysosomal rather than proteasomal pathway in macrophages. Suppression of the lysosomal degradation of iNOS by bafilomycin A1 drove septic cardiac dysfunction in myeloid HO-1–deficient mice. Mechanistically, we demonstrated that HO-1 interacted with iNOS at the flavin mononucleotide domain, which further prevented iNOS conjugation with LC3 (light chain 3) and subsequent lysosomal degradation in macrophages. These effects were independent of HO-1’s catabolic products: ferrous ion, carbon monoxide, and bilirubin. Conclusions: Our results indicate that HO-1 in macrophages drives septic cardiac dysfunction. The mechanistic insights provide potential therapeutic targets to treat septic cardiac dysfunction.