Antifibrotic cardioprotection of berberine via downregulating myocardial IGF-1 receptor-regulated MMP-2/MMP-9 expression in diabetic rats
Antifibrotic cardioprotection of berberine via downregulating myocardial IGF-1 receptor-regulated MMP-2/MMP-9 expression in diabetic rats
复制标题
小檗碱通过下调糖尿病大鼠心肌 IGF-1 受体调节的 MMP-2/MMP-9 表达来抗纤维化心脏保护。
DOI：
10.1152/ajpheart.00093.2018
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发表时间：
2018-10-01
影响因子：
4.8
通讯作者：
Gao, Feng
中科院分区：
文献类型：
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作者：
Li, Guohua;Xing, Wenjuan;Gao, Feng
糖尿病性心肌纤维化会增加心室僵硬度，促使舒张功能障碍的发生。我们之前的研究表明，黄连素这种天然生物碱可减轻糖尿病大鼠的心肌缺血 - 再灌注损伤。本研究旨在探讨长期使用黄连素对糖尿病大鼠心脏重塑的影响及其潜在机制。通过小剂量链脲佐菌素注射联合8周高脂饮食诱导的糖尿病大鼠，出现了明显的心脏基质胶原沉积和功能障碍，而给予黄连素（200毫克·千克⁻¹·天⁻¹，灌胃4周）可显著改善糖尿病大鼠的心肌纤维化和功能障碍，并降低心脏胰岛素样生长因子 - 1受体（IGF - 1R）的表达。有趣的是，从糖尿病心脏分离的心肌成纤维细胞或在高糖条件（30毫摩尔）下培养的心肌成纤维细胞中，IGF - 1R的表达上调。高糖处理或IGF - 1R过表达会增加心肌成纤维细胞中基质金属蛋白酶（MMP） - 2 / MMP - 9的表达、α - 平滑肌肌动蛋白（α - SMA）以及I型胶原蛋白的表达。相比之下，黄连素处理显著抑制了高糖培养的心肌成纤维细胞中IGF - 1R的表达，并发挥抗纤维化作用，表现为MMP - 2 / MMP - 9、α - SMA和I型胶原蛋白表达的降低，而与单独使用黄连素处理相比，IGF - 1R小干扰RNA联合黄连素处理并未进一步增强这种抗纤维化作用。综上所述，长期使用黄连素通过下调心肌成纤维细胞中IGF - 1R的表达，进而降低糖尿病心脏中MMP - 2 / MMP - 9、α - SMA和I型胶原蛋白的表达，从而改善心肌纤维化和功能障碍。这些研究结果表明黄连素对伴有心肌纤维化的糖尿病心肌病具有治疗潜力。
**新发现与要点**：黄连素下调了心肌成纤维细胞中IGF - 1受体的表达以及基质金属蛋白酶 - 2 / 基质金属蛋白酶 - 9的水平，从而抑制了糖尿病心脏中成纤维细胞的分化和胶原蛋白的过度生成，这为黄连素在2型糖尿病中发挥抗纤维化心脏保护作用提出了一种新机制。
Diabetic cardiac fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction. Our previous studies have shown that berberine, a natural alkaloid, attenuates cardiac ischemia-reperfusion injury in diabetic rats. The aim of present study was to investigate the effects of long-term berberine treatment on cardiac remodeling in diabetic rats and the underlying mechanisms. Diabetic rats induced by low-dose streptozotocin injection combined with 8 wk of high-fat diet displayed significant cardiac matrix collagen deposition and dysfunction, whereas berberine administration (200 mg·kg-1·day-1, gavage 4 wk) significantly ameliorated cardiac fibrosis and dysfunction and reduced cardiac IGF-1 receptor (IGF-1R) expression in diabetic rats. Interestingly, IGF-1R expression was upregulated in cardiac fibroblasts isolated from diabetic hearts or cultured in high-glucose conditions (30 mM). High glucose treatment or IGF-1R overexpression increased matrix metalloproteinase (MMP)-2/MMP-9 expression, α-smooth muscle actin (α-SMA), and collagen type I expression in cardiac fibroblasts. In contrast, berberine treatment significantly inhibited IGF-1R expression and exerted an antifibrotic effect in high glucose-cultured cardiac fibroblasts, as manifested by decreased MMP-2/MMP-9, α-SMA, and collagen type I expression, whereas IGF-1R siRNA plus berberine treatment did not further enhance this antifibrotic effect compared with berberine treatment alone. Taken together, long-term berberine treatment ameliorates cardiac fibrosis and dysfunction by downregulating IGF-1R expression in cardiac fibroblasts and subsequently reducing MMP-2/MMP-9, α-SMA, and collagen type I expression in diabetic hearts. The findings suggest the therapeutic potential of berberine for diabetic cardiomyopathy associated with cardiac fibrosis. NEW & NOTEWORTHY Berberine downregulated IGF-1 receptor expression and matrix metalloproteinase-2/matrix metalloproteinase-9 levels in cardiac fibroblasts and thus inhibited fibroblast differentiation and collagen overproduction in diabetic hearts, suggesting a novel mechanism for antifibrotic cardioprotection of berberine in type 2 diabetes.