title: Cardiac-specific overexpression of E3 ligase Nrdp1 increases ischemia and reperfusion-induced cardiac injury.
abstract: Cardiomyocyte death is a major event of myocardial infarction. Previously, we and others have shown that E3 ligase-mediated protein turnover plays a critical role in cardiac injury. In this study, we sought to determine the role of a newly identified E3 ligase, neuregulin receptor degradation protein-1 (Nrdp1), on cardiac ischemia/reperfusion (I/R) injury. I/R injury markedly upregulated Nrdp1 expression in heart tissue. To elucidate the role of Nrdp1 in I/R-induced cardiac injury, neonatal cardiomyocytes were infected with adenoviral constructs expressing wild-type, dominant-negative Nrdp1 genes. Increased Nrdp1 expression enhanced I/R-induced cardiomyocyte apoptosis and inflammation as compared with the green fluorescent protein (GFP) control; these effects were attenuated by overexpression of a dominant-negative Nrdp1 (C34S/H36Q). Furthermore, cardiac-specific Nrdp1 overexpression in vivo in mouse significantly increased infarct size, the number of TUNEL-positive nuclei and inflammatory cells, as well as mortality, as compared with wild-type mice after I/R injury. The mechanisms underlying these effects were associated with the downregulation of an Nrdp1 substrate, ErbB3, accompanied by suppression of its downstream targets AKT, ERK1/2, and activation of p38 and JNK1/2. Together, these results provide evidence for an important role for Nrdp1 in regulating I/R-induced cardiac injury. Nrdp1 may constitute a new therapeutic target for ameliorating the I/R-induced cardiac injury.
authors.affiliation: Department of Pathology, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zeng
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Cui
authors.initials: C
authors.lastname: Tian
authors.forename: Xu
authors.initials: X
authors.lastname: Ma
authors.forename: Houzao
authors.initials: H
authors.lastname: Chen
authors.forename: Quan
authors.initials: Q
authors.lastname: Fang
authors.forename: Lixin
authors.initials: L
authors.lastname: Jia
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; C435904:Rnf41 protein, mouse; D044767:Ubiquitin-Protein Ligases