Caspase-1 mediates hyperlipidemia-weakened progenitor cell vessel repair.
Caspase-1 mediates hyperlipidemia-weakened progenitor cell vessel repair.
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DOI：
10.2741/4383
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发表时间：
2016-01-01
期刊：
影响因子：
--
通讯作者：
Yang XF
中科院分区：
文献类型：
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作者：
Li YF;Huang X;Li X;Gong R;Yin Y;Nelson J;Gao E;Zhang H;Hoffman NE;Houser SR;Madesh M;Tilley DG;Choi ET;Jiang X;Huang CX;Wang H;Yang XF
半胱天冬酶-1激活感知代谢性炎症相关分子模式（DAMP）并介导内皮细胞中炎症的起始。在这里，我们研究了胱天蛋白酶-1途径是否负责在骨髓（BM）衍生的干细胞抗原-1阳性（Sca-1+）干/祖细胞中作为DAMP感知高脂血症并削弱其血管生成能力。本研究采用生物化学方法、基因敲除、细胞治疗和心肌梗死（MI）模型，发现：1）高血压在体内可诱导小鼠Sca-1+祖细胞caspase-1的活性，2）Caspase-1参与了高血压诱导的血管细胞死亡相关基因表达的调节，3）Caspase-1参与了高血压诱导的血管细胞死亡相关基因表达的调节，4）Caspase-1参与了高血压诱导的血管细胞死亡相关基因表达的调节。3）注射来自caspase-1−/−小鼠的Sca-1+祖细胞改善心肌梗死小鼠模型中心脏的内皮毛细血管密度并减少心肌细胞死亡; Caspase-1−/− Sca-1+祖细胞疗法改善MI后小鼠心脏功能。我们的研究结果提供了关于高脂血症如何激活Sca-1+祖细胞中的caspase-1，从而削弱Sca-1+祖细胞对血管损伤的修复的见解。这些结果证明了半胱天冬酶-1抑制在改善MI的祖细胞治疗中的治疗潜力。
Caspase-1 activation senses metabolic danger-associated molecular patterns (DAMPs) and mediates the initiation of inflammation in endothelial cells. Here, we examined whether the caspase-1 pathway is responsible for sensing hyperlipidemia as a DAMP in bone marrow (BM)-derived Stem cell antigen-1 positive (Sca-1+) stem/progenitor cells and weakening their angiogenic ability. Using biochemical methods, gene knockout, cell therapy and myocardial infarction (MI) models, we had the following findings: 1) Hyperlipidemia induces caspase-1 activity in mouse Sca-1+ progenitor cells in vivo; 2) Caspase-1 contributes to hyperlipidemia-induced modulation of vascular cell death-related gene expression in vivo; 3) Injection of Sca-1+ progenitor cells from caspase-1−/− mice improves endothelial capillary density in heart and decreases cardiomyocyte death in a mouse model of MI; and 4) Caspase-1−/− Sca-1+ progenitor cell therapy improves mouse cardiac function after MI. Our results provide insight on how hyperlipidemia activates caspase-1 in Sca-1+ progenitor cells, which subsequently weakens Sca-1+ progenitor cell repair of vasculature injury. These results demonstrate the therapeutic potential of caspase-1 inhibition in improving progenitor cell therapy for MI.