Intrathecal lentivirus-mediated RNA interference targeting nerve growth factor attenuates myocardial ischaemia–reperfusion injury in rat

Abstract

Background: Nerve growth factor (NGF) has been implicated in hyperalgesia by sensitising nociceptors. A role for NGF in modulating myocardial injury through ischaemic nociceptive signalling is plausible. We examined whether inhibition of spinal NGF attenuates myocardial ischaemiaereperfusion injury and explored the underlying mechanisms. Methods: In adult rats, lentivirus-mediated short-hairpin RNA targeted at reducing NGF gene expression (NGF-shRNA) or a transient receptor potential vanilloid 1 (TRPV1) antagonist (capsazepine) was injected intrathecally before myocardial ischaemiaereperfusion. Infarct size (expressed as the ratio of area at risk) and risk of arrhythmias were quantified. Whole-cell clamp patch electrophysiology was used to record capsaicin currents in primary dorsal root ganglion neurones. The co-expression of substance P (SP) and calcitonin gene-related peptide (CGRP), plus activation of TRPV1, protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were also quantified. Results: NGF levels increased by 2.95 (0.34)-fold in dorsal root ganglion and 2.12 (0.27)-fold in spinal cord after myocardial ischaemiaereperfusion injury. Intrathecal injection of NGF-shRNA reduced infarct area at risk from 0.58 (0.02) to 0.37 (0.02) (P<0.01) and reduced arrhythmia score from 3.67 (0.33) to 1.67 (0.33) (P<0.01). Intrathecal capsazepine was similarly cardioprotective. NGF-shRNA suppressed expression of SP/CGRP and activation of Akt/ERK and TRPV1 in spinal cord. NGF increased capsaicin current amplitude from 144 (42) to 840 (132) pA (P<0.05), which was blocked by the TRPV1 antagonist 5 0-iodoresiniferatoxin. Exogenous NGF enhanced capsaicin-induced Akt/ERK and TRPV1 activation in PC12 neuroendocrine tumour cells in culture. Conclusions: Spinal NGF contributes to myocardial ischaemiaereperfusion injury by mediating nociceptive signal transmission.

RRM2 Improves Cardiomyocyte Proliferation after Myocardial Ischemia Reperfusion Injury through the Hippo-YAP Pathway

“…Studies have confirmed that the cardiomyocyte H/R model can be used as an effective method to simulate myocardial I/RI in the cardiomyocyte culture model [ 17 ]. And the duration of hypoxia is a crucial factor for the success of the H/R model.…”

Transient Receptor Potential channels: A Global Bibliometric analysis From 2012 to 2021

“…TRPV1 also affects circulation through the spinal cord neurons and DRG neurons. The experiment shows that on the myocardial ischemia-reperfusion, additional activation of the spinal cord TRPV1 contributed to a severer myocardial injury; however, intrathecal administration of the TRPV1 antagonist capsazepine reduced the size of the infarct area [ 23 ].…”

Capsaicin-Sensitive Sensory Nerves and the TRPV1 Ion Channel in Cardiac Physiology and Pathologies

“…Nerve growth factor (NGF) has a key role in upregulating TRPV1 expression in peptidergic sensory neurons of adult rats [ 83 ] via the NGF-TrkA signaling. Knocking down spinal NGF had myocardial protective effect against ischemic injury similarly to the effect of capsazepine in a rat AMI model [ 84 , 85 ]. However, it is important to note that the sample size used in these studies were low, n = 3 and n = 6, respectively.…”