title: Targeted P2X7R shRNA delivery attenuates sympathetic nerve sprouting and ameliorates cardiac dysfunction in rats with myocardial infarction.
abstract: BACKGROUND
  Inflammation-dominated sympathetic sprouting adjacent to the necrotic region following myocardial infarction (MI) has been implicated in the etiology of arrhythmias resulting in sudden cardiac death; however, the mechanisms responsible remain to be elucidated. Although P2X7R is a key immune mediator, its role has yet to be explored.
  
  
  OBJECTIVE
  We investigated whether P2X7R regulates NF-κB and affects cardiac sympathetic reinnervation in rats undergoing MI.
  
  
  RESULTS
  An adenoviral vector with a short hairpin RNA (shRNA) sequence inserted was adopted for the inhibition of P2X7R in vivo. Myocardial infarction was induced by left coronary artery ligation, and immediately after that, recombinant P2X7R-shRNA adenovirus, negative adenovirus (control), or normal saline solution (vehicle) was injected intramyocardially around the MI region and border areas. A high level of P2X7R was activated in the infarcted tissue at an early stage. The administration of P2X7R RNAi resulted in the inhibition of Akt and Erk1/2 phosphorylation and decreased the activation of NF-κB and macrophage infiltration, as well as attenuated the expression of nerve growth factor (NGF). Eventually, the NGF-induced sympathetic hyperinnervation was blunted, as assessed by the immunofluorescence of tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP 43). At 7 days post-MI, the arrhythmia score of programmed electrical stimulation in the vehicle-treated infarcted rats was higher than the MI-shRNA group. Further amelioration of cardiac dysfunction was also detected.
  
  
  CONCLUSIONS
  The administration of P2X7R RNAi during the acute inflammatory response phase prevented the process of sympathetic hyperinnervation after MI, which was associated in part with inhibiting the Akt and ERK1/2 pathways and NF-κB activation.
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.|Department of Cardiology, Shandong Provincial Corps Hospital, Chinese People's Armed Police Force, Jinan, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Yugen
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Hesheng
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Xue
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Xinran
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Yongkang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Suhua
authors.identifier: http://orcid.org/0000-0002-7746-6787
authors.initials: S
authors.lastname: Yan
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019922:GAP-43 Protein / Q000378:metabolism; D005822:Genetic Vectors; D006321:Heart / Q000294:innervation*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D055495:Neurogenesis; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D000067492:RNAi Therapeutics / Q000379:methods*; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000254:growth & development* / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D019922:GAP-43 Protein; D016328:NF-kappa B; D034741:RNA, Small Interfering; D058486:Receptors, Purinergic P2X7; D020932:Nerve Growth Factor; D014446:Tyrosine 3-Monooxygenase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Myocardial infarction; NF-κB; P2X7R; Sympathetic hyperinnervation