School of Aerospace Medicine, Fourth Military Medical University , Xi'an , China.
Experimental Teaching Center, Fourth Military Medical University , Xi'an , China.
Am J Physiol Heart Circ Physiol. 2018 Oct 1;315(4):H802-H813. doi: 10.1152/ajpheart.00093.2018. Epub 2018 Jun 29.
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·day, 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.
糖尿病性心脏纤维化增加心室僵硬度，促进舒张功能障碍的发生。我们之前的研究表明，小檗碱是一种天然生物碱，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小檗碱治疗对糖尿病大鼠心脏重构的影响及其机制。低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表现出明显的心脏基质胶原沉积和功能障碍，而小檗碱给药（200mg·kg·天，灌胃 4 周）可显著改善糖尿病大鼠的心脏纤维化和功能障碍，并降低心脏 IGF-1 受体（IGF-1R）表达。有趣的是，IGF-1R 在糖尿病心脏来源的成纤维细胞或在高糖条件（30mM）下培养的成纤维细胞中表达上调。高糖处理或 IGF-1R 过表达增加了基质金属蛋白酶（MMP）-2/MMP-9、α-平滑肌肌动蛋白（α-SMA）和胶原 I 的表达。相反，小檗碱处理显著抑制了高糖培养的成纤维细胞中 IGF-1R 的表达，并发挥了抗纤维化作用，表现为 MMP-2/MMP-9、α-SMA 和胶原 I 的表达减少，而 IGF-1R siRNA 联合小檗碱处理与单独小檗碱处理相比并未进一步增强这种抗纤维化作用。总之，长期小檗碱治疗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 和胶原 I 的表达，改善心脏纤维化和功能障碍。这些发现提示小檗碱治疗 2 型糖尿病相关心脏纤维化的潜在治疗价值。
