Targeted P2X₇ R shRNA delivery attenuates sympathetic nerve sprouting and ameliorates cardiac dysfunction in rats...

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 P2X₇ R is a key immune mediator, its role has yet to be explored.

We investigated whether P2X₇ R regulates NF-κB and affects cardiac sympathetic reinnervation in rats undergoing MI.

An adenoviral vector with a short hairpin RNA (shRNA) sequence inserted was adopted for the inhibition of P2X₇ R in vivo. Myocardial infarction was induced by left coronary artery ligation, and immediately after that, recombinant P2X₇ R-shRNA adenovirus, negative adenovirus (control), or normal saline solution (vehicle) was injected intramyocardially around the MI region and border areas. A high level of P2X₇ R was activated in the infarcted tissue at an early stage. The administration of P2X₇ R 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.

The administration of P2X₇ R 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.