Abstract 424: Knockdown of Nerve Growth Factor in Spinal Cord Reduces Myocardial Reperfusion Injury by Suppressing Ischemic Nociceptive Signaling Transmission

Abstract

Objective: To test the hypothesis that nerve growth factor (NGF) sensitized spinal cardiac afferent activity contributes to myocardial ischemia-reperfusion injury (IRI). Methods and Results: The expression levels of NGF were increased in both dorsal root ganglion (DRG) and spinal cord after myocardial IRI in rats. Whole-cell patch clamp in cultured DRG neurons revealed that NGF aggravated capsaicin-induced current which was eliminated by the transient receptor potential vanilloid 1 (TRPV1) antagonist. Intrathecal injection of lentivirus-mediated NGF shRNA into thoracic T1-T8 segments successfully suppressed NGF mRNA and protein levels. Knockdown of NGF in spinal cord significantly limited IRI-induced infarct size, lowered down the concentration of cardiac troponin I (cTnI), and improved arrhythmia score. NGF gene suppression markedly reduced IRI-caused elevation of NGF and its receptor tropomyosin receptor kinase A (TrkA), TRPV1 and phosphorylated TRPV1. The activation of protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) was also inhibited by NGF shRNA. Upon immunofluorescence staining, substance P (SP) and calcitonin gene-related peptide (CGRP) were found strongly stained in DRG and spinal dorsal horn following myocardial IRI, while these immunoreactive staining were repressed due to NGF gene knockdown. Conclusions: NGF aggravated spinal cardiac afferent nerves activity by sensitizing TRPV1-mediated nociceptive signal transmission. Inhibition of spinal NGF expression effectively protected the heart from myocardial IRI, which may imply a new potential therapeutic approach in ischemic heart diseases.