瑞舒伐他汀通过抑制 2 型糖尿病大鼠模型中的 NLRP3 炎性小体和 MAPK 通路来缓解糖尿病心肌病。

Rosuvastatin alleviates diabetic cardiomyopathy by inhibiting NLRP3 inflammasome and MAPK pathways in a type 2 diabetes rat model.

机构信息

The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, No.107, Wen Hua Xi Road, Jinan, Shandong, 250012, People's Republic of China.

出版信息

Cardiovasc Drugs Ther. 2014 Feb;28(1):33-43. doi: 10.1007/s10557-013-6498-1.

DOI:10.1007/s10557-013-6498-1

PMID:24254031

Abstract

PURPOSE

Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is important in inflammation of several diabetic complications. However, the potential role of NLRP3 inflammasome in the inflammatory process of diabetic cardiomyopathy (DCM) remains unclear. Although rosuvastatin (RSV) has an anti-inflammatory effect on some cardiovascular diseases, its influence on DCM is incompletely understood. We aimed to explore the effect on and underlying mechanism of RSV in DCM, and whether NLRP3 is a target for RSV.

METHODS

Type 2 diabetes was induced in rat. The characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. The expression of factors was determined by real-time RT-PCR and western blot. Eight-week RSV treatment and NLRP3 gene silencing were used to investigate the effect and underlying target of RSV in DCM.

RESULTS

Compared with controls, diabetic rats showed severe metabolic disorder, cardiac dysfunction, fibrosis, disorganized ultrastructure, and excessive activation of thioredoxin interacting/inhibiting protein (TXNIP, p < 0.05), NLRP3 inflammasome (NLRP3, p < 0.01; apoptosis-associated speck-like protein containing a caspase recruitment domain [ASC], p < 0.05; caspase-1, p < 0.01), interleukin-1β (p < 0.01) and mitogen-activated protein kinases (MAPKs, all p < 0.01). Compared with diabetes alone, RSV ameliorated the overexpression of NLRP3 inflammasome (NLRP3, p < 0.05; ASC, p < 0.05; pro-caspase-1 p < 0.05, caspase-1 p20, p < 0.01) and MAPKs (all p < 0.05), which paralleled the cardiac protection of RSV. Silencing NLRP3 ameliorated cardiac remodeling and dysfunction. The beneficial effects of RSV in vehicle-treated rats were all abrogated in NLRP3-silenced rats.

CONCLUSIONS

The beneficial effect of RSV on DCM depended on inhibited NLRP3 inflammasome, and correlated with suppression of the MAPKs.

摘要

目的

核苷酸结合寡聚化结构域样受体蛋白 3（NLRP3）炎性小体在几种糖尿病并发症的炎症中起重要作用。然而，NLRP3 炎性小体在糖尿病心肌病（DCM）炎症过程中的潜在作用尚不清楚。虽然瑞舒伐他汀（RSV）对一些心血管疾病具有抗炎作用，但对 DCM 的影响尚不完全清楚。我们旨在探讨 RSV 在 DCM 中的作用及其潜在机制，以及 NLRP3 是否是 RSV 的靶点。

方法

在大鼠中诱导 2 型糖尿病。通过代谢试验、超声心动图和组织病理学评估 2 型 DCM 的特征。通过实时 RT-PCR 和 Western blot 确定因子的表达。采用 8 周 RSV 治疗和 NLRP3 基因沉默来研究 RSV 在 DCM 中的作用及其潜在靶点。

结果

与对照组相比，糖尿病大鼠表现出严重的代谢紊乱、心脏功能障碍、纤维化、超微结构紊乱和硫氧还蛋白相互作用/抑制蛋白（TXNIP，p<0.05）、NLRP3 炎性小体（NLRP3，p<0.01；凋亡相关斑点样蛋白含有半胱氨酸天冬氨酸蛋白酶募集域 [ASC]，p<0.05；半胱天冬酶-1，p<0.01）、白细胞介素-1β（p<0.01）和丝裂原活化蛋白激酶（MAPKs，均 p<0.01）过度激活。与单纯糖尿病相比，RSV 改善了 NLRP3 炎性小体（NLRP3，p<0.05；ASC，p<0.05；前半胱天冬酶-1，p<0.05，半胱天冬酶-1 p20，p<0.01）和 MAPKs（均 p<0.05）的过度表达，这与 RSV 的心脏保护作用相一致。沉默 NLRP3 可改善心脏重塑和功能障碍。在沉默 NLRP3 的大鼠中，RSV 在载体处理的大鼠中的有益作用均被消除。