Cardiovascular Drugs and Therapy

, Volume 28, Issue 1, pp 33–43

Rosuvastatin Alleviates Diabetic Cardiomyopathy by Inhibiting NLRP3 Inflammasome and MAPK Pathways in a Type 2 Diabetes Rat Model

  • Beibei Luo
  • Bo Li
  • Wenke Wang
  • Xiangjuan Liu
  • Xiaoman Liu
  • Yanfei Xia
  • Cheng Zhang
  • Yun Zhang
  • Mingxiang Zhang
  • Fengshuang An
ORIGINAL ARTICLE

DOI: 10.1007/s10557-013-6498-1

Cite this article as:
Luo, B., Li, B., Wang, W. et al. Cardiovasc Drugs Ther (2014) 28: 33. doi:10.1007/s10557-013-6498-1

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.

Keywords

DCMRosuvastatinNLRP3 inflammasomeGene silencingMAPKs

Supplementary material

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Supplementary Fig. 1

Rosuvastatin (RSV) alleviated diabetes mellitus (DM)-induced left-ventricular dysfunction. Evaluation of cardiac function parameters; (a) LVEF; (b) FS; (c) E/A; (d) E′/A′. Data are mean ± SEM. n = 6–8 per group. *p < 0.05, **p < 0.01 vs. control; ##p < 0.01 vs. HF; p < 0.05 vs. DM. (JPEG 168 kb)

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Supplementary Fig. 2

RSV attenuated pathological changes in the heart of DM rats. (a) Heart weight to body weight; (b) Fibrosis area to total area; (c-d) mRNA expression of collagen I and III and (e) ratio of collagen I to collagen III. Data are mean ± SEM. n = 6–8 per group. *p < 0.05, **p < 0.01 vs. control; #p < 0.05, ##p < 0.01 vs. HF; p < 0.05, ††p < 0.01 vs. DM; bp < 0.05, bbp < 0.01 vs. DM + RSV 10 mg/kg. (JPEG 190 kb)

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Supplementary Fig. 3

RSV suppressed the protein levels of TXNIP, NLRP3 inflammasome and IL-1β in DM rats. Quantification of western blot results in Fig. 4. Data are mean ± SEM. n = 7–9 per group. *p < 0.05, **p < 0.01 vs. control; #p < 0.05, ##p < 0.01 vs. HF; p < 0.05, ††p < 0.01 vs. DM; ap < 0.05, aap < 0.01 vs. HF + RSV 10 mg/kg; bbp < 0.01 vs. DM + RSV 10 mg/kg. (JPEG 211 kb)

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Supplementary Fig. 4

Transfection of NLRP3-miRNA was effective in myocardial tissue. Bright green points (white arrow) indicate GFP with lentivirus-NLRP3-miRNA or vehicle transfection (scale bar: 50 μm). n = 8–10 per group. (JPEG 118 kb)

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Supplementary Fig. 5

RSV improved NLRP3-dependent cardiac dysfunction in DM. Evaluation of LVEF (a), FS (b), E/A (c), E′/A′ (d). Data are mean ± SEM. n = 8–10 per group. *p < 0.05, **p < 0.01 vs. vehicle + control; p < 0.05 vs. vehicle + DM; cp < 0.05 vs. vehicle + DM + RSV 15 mg/kg. (JPEG 156 kb)

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Supplementary Fig. 6

RSV improved NLRP3-dependent cardiac disorder in diabetes. (a) Ratio of heart weight to body weight; (b) fibrosis area to total area ratio; (c-d) mRNA expression of collagen I and III, (e) and ratio of collagen I to collagen III. Data are mean ± SEM. n = 6–8 per group. *p < 0.05, **p < 0.01 vs. vehicle + control; p < 0.05, ††p < 0.01 vs. vehicle + DM; cp < 0.05, ccp < 0.01 vs. vehicle + DM + RSV 15 mg/kg. (JPEG 262 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Beibei Luo
    • 1
  • Bo Li
    • 1
  • Wenke Wang
    • 1
  • Xiangjuan Liu
    • 1
  • Xiaoman Liu
    • 1
  • Yanfei Xia
    • 1
  • Cheng Zhang
    • 1
  • Yun Zhang
    • 1
  • Mingxiang Zhang
    • 1
  • Fengshuang An
    • 1
  1. 1.The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of HealthShandong University Qilu HospitalJinanPeople’s Republic of China