Protective effects of triptolide on TLR4 mediated autoimmune and inflammatory response induced myocardial fibrosis in diabetic cardiomyopathy

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• 作者：Xin Guo ; Mei Xue ; Chun-jun Li ; Wei Yang ; Shan-shan Wang ; Ze-jun Ma ; Xiao-na Zhang ; Xiao-yu Wang ; Ran Zhao ; Bao-cheng Chang ; Li-ming Chen ; ^{xfx22081@vip.163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：α-SMA ; α-Smooth muscle actin ; DCM ; diabetic cardiomyopathy ; DM ; Diabetes mellitus ; DN ; diabetic nephropathy ; EF ; Ejection fraction ; ECM ; Extra cellular matrix ; FS ; fractional shortening ; IL-1β ; Interleukin-1β ; LV ; Left ventricle ; LVEDD ; Left ventricular end-diastolic dimension ; NF-κB ; Nuclear factor-kappa B ; MCP-1 ; Monocyte chemotactic protein-1 ; STZ ; Streptozocin ; TwHF ; Tripterygium wilfordii Hook F ; TLR4 ; Toll-like receptors 4 ; TNF-α ; Tumor necrosis factor-α ; TGF-β1 ; Transforming growth factor
• 刊名：Journal of Ethnopharmacology
• 出版年：2016
• 出版时间：4 December 2016
• 年：2016
• 卷：193
• 期：Complete
• 页码：333-344
• 全文大小：12438 K

文摘

Triptolide is a most important active ingredient extracted from traditional Chinese medicine Tripterygium, which has been widely used to treat glomerulonephritis as well as immune-mediated disorders, likely for its immunosuppressive, anti-proliferative and anti-inflammatory effects.

Aim of the study

In this study, we have investigated the potential protective effects of triptolide against diabetic cardiomyopathy (DCM) by regulating immune system, attenuating inflammatory response, thus resulting in decreased cardiac fibrosis and improved left ventricle function.

Materials and methods

Sprague-Dawley rats were randomly divided into 5 groups: normal group, diabetic group and diabetic rats treated with triptolide (50, 100, or 200 μg/kg/day resp) for 8 weeks. Cardiac function was performed by echocardiography and histopathology of the hearts was examined with HE, Masson staining and scanning electron microscopy. Immune regulation mediator, macrophage infiltration, inflammatory response and cardiac fibrosis related cytokines were measured by RT-PCR, Western blot and Immunohistochemistry staining.

Results

In the diabetic group, the expressions of TLR4 and NF-κB p65 were both up-regulated, which was associated with increased pro-inflammatory cytokines, coupled with cardiac fibrosis and impaired left ventricular function. Interestingly, pathological structure and function of left ventricle were both significantly improved in the triptolide treated groups. Furthermore, the immune mediator TLR4, downstream activator NF-κB p65, macrophage infiltration (CD68+), pro-inflammatory cytokines (TNF-α, IL-1β), cell adhesion molecule (VCAM-1) and chemokine (MCP-1) were significantly suppressed when treated with medium and high dosage triptolide compared with the diabetic group. Moreover, cardiac fibrosis pathway including α-SMA, TGF-β1, vimentin and collagen accumulations were observed significantly decreased in the triptolide treated groups.

Conclusions

Our data demonstrated that the protective effects of triptolide against DCM might attribute to inhibition of TLR4-induced NF-κB/IL-1β immune pathway, suppression of NF-κB/TNF-α/VCAM-1 inflammatory pathway and down-regulation of TGF-β1/α-SMA/Vimentin fibrosis pathway.