Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands; Department of Pathology and Department of Molecular Genetics, CARIM, Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
Atherosclerosis. 2018 Aug;275:156-165. doi: 10.1016/j.atherosclerosis.2018.05.052. Epub 2018 Jun 1.
Atherosclerosis is a lipid-driven chronic inflammatory disorder of the arteries, and monocytes and macrophages play a central role in this process. Within the atherosclerotic lesion, macrophages can scavenge modified lipids and become the so-called foam cells. We previously reported that the epigenetic enzyme Kdm6b (also known as Jmjd3) controls the pro-fibrotic transcriptional profile of peritoneal foam cells. Given the importance of these cells in atherosclerosis, we now studied the effect of myeloid Kdm6b on disease progression.
Bone marrow of myeloid Kdm6b deficient (Kdm6b) mice or wild type littermates (Kdm6b) was transplanted to lethally irradiated Ldlr mice fed a high fat diet for 9 weeks to induce atherosclerosis.
Lesion size was similar in Kdm6b and Kdm6b transplanted mice. However, lesions of Kdm6b mice contained more collagen and were more necrotic. Pathway analysis on peritoneal foam cells showed that the pathway involved in leukocyte chemotaxis was most significantly upregulated. Although macrophage and neutrophil content was similar after 9 weeks of high fat diet feeding, the relative increase in collagen content and necrosis revealed that atherosclerotic lesions in Kdm6b mice progress faster.
Myeloid Kdm6b deficiency results in more advanced atherosclerosis.
动脉粥样硬化是一种由脂质驱动的动脉慢性炎症性疾病，单核细胞和巨噬细胞在这个过程中起核心作用。在动脉粥样硬化病变中，巨噬细胞可以吞噬修饰后的脂质，成为所谓的泡沫细胞。我们之前报道过，表观遗传酶 Kdm6b（也称为 Jmjd3）控制着腹膜泡沫细胞的促纤维化转录特征。鉴于这些细胞在动脉粥样硬化中的重要性，我们现在研究了髓样细胞 Kdm6b 对疾病进展的影响。
将骨髓来源的 Kdm6b 缺陷型（Kdm6b）小鼠或野生型同窝仔鼠（Kdm6b）的骨髓移植到接受高脂肪饮食喂养 9 周以诱导动脉粥样硬化的致死性辐射 Ldlr 小鼠中。
Kdm6b 和 Kdm6b 移植小鼠的病变大小相似。然而，Kdm6b 小鼠的病变含有更多的胶原，并且更坏死。对腹膜泡沫细胞的通路分析表明，白细胞趋化通路被显著上调。尽管在高脂肪饮食喂养 9 周后，巨噬细胞和中性粒细胞含量相似，但胶原含量和坏死的相对增加表明 Kdm6b 小鼠的动脉粥样硬化病变进展更快。
髓样细胞 Kdm6b 缺乏导致更严重的动脉粥样硬化。
