title: Rosuvastatin alleviates diabetic cardiomyopathy by inhibiting NLRP3 inflammasome and MAPK pathways in a type 2 diabetes rat model.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Beibei
authors.initials: B
authors.lastname: Luo
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Wenke
authors.initials: W
authors.lastname: Wang
authors.forename: Xiangjuan
authors.initials: X
authors.lastname: Liu
authors.forename: Xiaoman
authors.initials: X
authors.lastname: Liu
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Xia
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Zhang
authors.forename: Fengshuang
authors.initials: F
authors.lastname: An
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins; D020170:Caspase 1 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy*; D005464:Fluorobenzenes / Q000494:pharmacology*; D020868:Gene Silencing; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D020928:Mitogen-Activated Protein Kinases; D020170:Caspase 1