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

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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.

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Acknowledgments

This study was supported by the National 973 Basic Research program (2009CB521904) and the grant of Natural Science Foundation of Shandong Province (Y2007C074).

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Corresponding authors

Correspondence to Mingxiang Zhang or Fengshuang An.

Electronic 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)

High Resolution Image (TIFF 5793 kb)

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)

High Resolution Image (TIFF 1272 kb)

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)

High Resolution Image (TIFF 5792 kb)

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)

High Resolution Image (TIFF 14520 kb)

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)

High Resolution Image (TIFF 5794 kb)

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)

High Resolution Image (TIFF 1562 kb)

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Luo, B., Li, B., Wang, W. et al. Rosuvastatin Alleviates Diabetic Cardiomyopathy by Inhibiting NLRP3 Inflammasome and MAPK Pathways in a Type 2 Diabetes Rat Model. Cardiovasc Drugs Ther 28, 33–43 (2014). https://doi.org/10.1007/s10557-013-6498-1

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