Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression.
Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression.
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DOI：
10.1371/journal.pone.0149288
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Tsao PS
中科院分区：
文献类型：
--
作者：
Azuma J;Wong RJ;Morisawa T;Hsu M;Maegdefessel L;Zhao H;Kalish F;Kayama Y;Wallenstein MB;Deng AC;Spin JM;Stevenson DK;Dalman RL;Tsao PS
血红素加氧酶-1（HO-1）是血红素降解的限速酶，是一种细胞保护酶，在血管系统中通过增加流量和炎症刺激而上调。人类遗传学数据表明，HO-1表达减少可能使腹主动脉瘤（AAA）的发展。此外，已知血红素强烈诱导HO-1表达。利用猪胰腺弹性蛋白酶（PPE）模型在HO-1杂合（HO-1+/-，HO-1 Het）小鼠中诱导AAA，我们发现HO-1的缺乏导致AAA发展增强。来自HO-1+/-小鼠的腹膜巨噬细胞显示促炎细胞因子（包括MCP-1、TNF-α、IL-1-β和IL-6）的基因表达增加，但抗炎细胞因子IL-10和TGF-β的表达减少。此外，血红素治疗使HO-1 Het小鼠的AAA进展恢复到野生型特征。使用第二种小鼠AAA模型（Ang II-ApoE-/-），我们发现低剂量的HMG-CoA还原酶抑制剂瑞舒伐他汀可以诱导主动脉组织中HO-1的表达，并在不降脂的情况下抑制AAA进展。我们的研究结果支持了他汀类药物的多效性可能通过上调HO-1而对AAA有益的研究。诱导HO-1的特异性靶向治疗可能成为预防AAA疾病的一种有效治疗策略。
Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease.