title: TIPE2 acts as a negative regulator linking NOD2 and inflammatory responses in myocardial ischemia/reperfusion injury.
abstract: Although recent studies have highlighted the importance of innate pattern-recognition receptors (PRRs) in the pathogenesis of cardiovascular diseases by mediating inflammatory responses, their molecular mechanisms of PRRs in cardiovascular diseases are still largely unknown. The present study was designed to explore the contribution of NOD2, an intracellular PRR, to the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. We found that NOD2 was upregulated in ischemic myocardium and NOD2 deficiency ameliorated cardiac injury in myocardial I/R mice accompanied by the decreased levels of pro-inflammatory mediators and cardiac inflammatory cell infiltration. We further found that TIPE2, a recently identified immune regulator, was negatively mediated by NOD2. In vitro, we demonstrated that TIPE2 inhibited NOD2-induced activation of MAPK and NF-κB signaling pathways, thereby reducing the production of pro-inflammatory cytokines in macrophages. Finally, in vivo gene silencing of TIPE2 by lentiviral gene delivery counteracted the reduced inflammation and myocardial injury in NOD2-deficient ischemic mice. Collectively, this study for the first time demonstrates that TIPE2 serves as a negative regulator of immunity, at least in part, by NOD2-mediated inflammatory responses in I/R-induced myocardial injury. A better understanding of NOD2-TIPE2 signaling pathways will provide unexpected opportunities for developing new therapies for ischemic cardiovascular disease.
  
  
  CONCLUSIONS
  NOD2 deficiency ameliorates myocardial ischemia reperfusion injury. NOD2 deficiency reduces the inflammatory response after myocardial I/R. TIPE2 inhibits NOD2-induced activation of MAPK and NF-κB signaling pathways. TIPE2 silencing counteracts the reduced inflammation and myocardial injury in NOD2(-/-) ischemic mice. TIPE2 acts as a negative regulator linking NOD2 and inflammatory responses.
authors: Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong, 250012, People's Republic of China.|Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, 250012, China.
authors: Hongyu
authors: H
authors: Zhang
authors: Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong, 250012, People's Republic of China.
authors: Tianfeng
authors: T
authors: Zhu
authors: Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong, 250012, People's Republic of China.
authors: Wenwen
authors: W
authors: Liu
authors: Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, 250012, China.
authors: Xin
authors: X
authors: Qu
authors: Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong, 250012, People's Republic of China.
authors: Ye
authors: Y
authors: Chen
authors: Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong, 250012, People's Republic of China.
authors: Ping
authors: P
authors: Ren
authors: Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong, 250012, People's Republic of China.
authors: Ziying
authors: Z
authors: Wang
authors: Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong, 250012, People's Republic of China.
authors: Xinbing
authors: X
authors: Wei
authors: Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong, 250012, People's Republic of China. zhangyan1978@sdu.edu.cn.
authors: Yan
authors: Y
authors: Zhang
authors: Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong, 250012, People's Republic of China. fanyi@sdu.edu.cn.
authors: Fan
authors: F
authors: Yi
mesh_terms: D000818:Animals; D002460:Cell Line; D005434:Flow Cytometry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C529002:TIPE2 protein, mouse
keywords: Inflammatory response; Ischemic myocardial injury; Nod-like receptors; TNFAIP8 family