Replacement of Lost Substance P Reduces Fibrosis in the Diabetic Heart by Preventing Adverse Fibroblast and Macrophage Phenotype Changes.
Replacement of Lost Substance P Reduces Fibrosis in the Diabetic Heart by Preventing Adverse Fibroblast and Macrophage Phenotype Changes.
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通过防止不良成纤维细胞和巨噬细胞表型的变化，替换失去的物质P可减少糖尿病心脏中的纤维化。
DOI：
10.3390/cells10102659
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发表时间：
2021-10-05
期刊：
影响因子：
6
通讯作者：
Levick SP
中科院分区：
文献类型：
--
作者：
Widiapradja A;Kasparian AO;McCaffrey SL;Kolb LL;Imig JD;Lacey JL;Melendez GC;Levick SP
据报道，糖尿病大鼠心脏中感觉神经肽P物质（SP）水平降低，其结果是响应缺血后处理的心脏保护作用丧失。我们考虑了SP的丢失是否也使心脏易患纤维化和肥大形式的非缺血性糖尿病心肌病。我们报告，糖尿病Leprdb/db小鼠血清SP降低，外源性SP替代管理改善心脏纤维化。Leprdb/db小鼠未发生心脏肥大。暴露于高葡萄糖的心脏成纤维细胞转化为肌成纤维细胞表型并产生过量的细胞外基质蛋白;培养基中存在SP可以防止这种情况。暴露于高糖的心脏成纤维细胞产生的晚期糖基化终产物、活性氧和炎性细胞因子的受体数量增加，所有这些都被SP阻止。培养的巨噬细胞呈现M1促炎表型，以响应高糖，如TNF-α、CCL 2和IL-6增加所示。SP促进了向修复性M2巨噬细胞表型的转变，该表型的特征在于由β-淀粉酶-1和IL-10。Leprdb/db小鼠显示左心室M1表型巨噬细胞增加和M1/M2比值增加。Leprdb/db小鼠中的替代SP恢复了有利的M1至M2平衡。总之，这些发现表明，SP的损失使糖尿病心脏易于发生纤维化。替代SP的抗纤维化作用涉及对心脏成纤维细胞和巨噬细胞的直接作用，以对抗不利的表型变化。这项研究确定了替代SP治疗糖尿病心肌病的潜力。
Reduced levels of the sensory nerve neuropeptide substance P (SP) have been reported in the diabetic rat heart, the consequence being a loss of cardioprotection in response to ischemic post-conditioning. We considered whether this loss of SP also predisposes the heart to non-ischemic diabetic cardiomyopathy in the form of fibrosis and hypertrophy. We report that diabetic Leprdb/db mice have reduced serum SP and that administration of exogenous replacement SP ameliorated cardiac fibrosis. Cardiac hypertrophy did not occur in Leprdb/db mice. Cardiac fibroblasts exposed to high glucose converted to a myofibroblast phenotype and produced excess extracellular matrix proteins; this was prevented by the presence of SP in the culture media. Cardiac fibroblasts exposed to high glucose produced increased amounts of the receptor for advanced glycation end products, reactive oxygen species and inflammatory cytokines, all of which were prevented by SP. Cultured macrophages assumed an M1 pro-inflammatory phenotype in response to high glucose as indicated by increased TNF-α, CCL2, and IL-6. SP promoted a shift to the reparative M2 macrophage phenotype characterized by arginase-1 and IL-10. Leprdb/db mice showed increased left ventricular M1 phenotype macrophages and an increase in the M1/M2 ratio. Replacement SP in Leprdb/db mice restored a favorable M1 to M2 balance. Together these findings indicate that a loss of SP predisposes the diabetic heart to developing fibrosis. The anti-fibrotic actions of replacement SP involve direct effects on cardiac fibroblasts and macrophages to oppose adverse phenotype changes. This study identifies the potential of replacement SP to treat diabetic cardiomyopathy.
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影响因子：
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作者：
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