Silencing of Pellino1 improves post-infarct cardiac dysfunction and attenuates left ventricular remodelling in mice.
OBJECTIVE
Pellino1 is an evolutionally conserved immune regulator and participates in the regulation of Toll-like receptor/interleukin-1 receptor (TLR/IL-1R)-mediated signalling. Recent studies have shown that TLR/IL-1R contributes to the left ventricular (LV) remodelling after myocardial infarction (MI). However, the role of Pellino1 in LV remodelling following MI has not been investigated. This study examined the effect of Pellino1 silencing on cardiac function and LV remodelling after MI.


RESULTS
Male C57BL/6 mice were subjected to permanent ligation of left anterior descending coronary artery (LAD) to induce MI. The levels of Pellino1 were significantly increased in the myocardium 3 days and sustained for 4 weeks after MI, when compared with the sham control. Hypoxia increased Pellino1 expression in cultured cardiomyocytes and fibroblasts. To examine whether Pellino1 plays a role in MI-induced cardiac dysfunction and the LV remodelling, we suppressed the expression of Pellino1 either by intramyocardial delivery of adenovirus expressing siRNA for Pellino1 (AdsiPeli1) or by Cre-LoxP-mediated conditional deletion of Pellino1 from the myocardium. In both models, silencing of Pellino1 significantly attenuated MI-induced cardiac dysfunction, decreased scar size, and reduced collagen deposition, when compared with the control groups. Pellino1 silencing in mice also attenuated MI-induced Pellino1 E3 ligase activity, receptor-interacting protein 1 and tumor necrosis factor receptor associated factor 6 (TRAF6) ubiquitination, nuclear factor Kappa B (NF-κB) activity, cytokine production, and inflammatory cell infiltration into the myocardium when compared with the MI group.


CONCLUSIONS
Our data demonstrate that Pellino1 plays an important role in the pathogenesis of MI. Targeting Pellino1 may ameliorate cardiac dysfunction and remodelling following MI.
Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China.
Wei
W
Wu
Yuanping
Y
Hu
Jiantao
J
Li
Weina
W
Zhu
Tuanzhu
T
Ha
Linli
L
Que
Li
L
Liu
Quan
Q
Zhu
Qi
Q
Chen
Yong
Y
Xu
Chuanfu
C
Li
Yuehua
Y
Li
D000818:Animals; D004195:Disease Models, Animal; D020868:Gene Silencing; D008297:Male; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000235:genetics* / Q000502:physiology
D009687:Nuclear Proteins; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D044767:Ubiquitin-Protein Ligases; C418046:Peli1 protein, mouse
Inflammation; Left ventricular remodelling; Myocardial infarction; Pellino1; TLR/IL-1R