Cardioprotection via the skin: nociceptor-induced conditioning against cardiac MI in the NIC of time

Abstract

Timely reperfusion is still the most effective approach to limit infarct size in humans. Yet, despite advances in care and reduction in door-to-balloon times, nearly 25% of patients develop heart failure postmyocardial infarction, with its attendant morbidity and mortality. We previously showed that cardioprotection results from a skin incision through the umbilicus in a murine model of myocardial infarction. In the present study, we show that an electrical stimulus or topical capsaicin applied to the skin in the same region induces significantly reduced infarct size in a murine model. We define this class of phenomena as nociceptor-induced conditioning (NIC) based on the peripheral nerve mechanism of initiation. We show that NIC is effective both as a preconditioning and postconditioning remote stimulus, reducing infarct size by 86% and 80%, respectively. NIC is induced via activation of skin C-fiber nerves. Interestingly, the skin region that activates NIC is limited to the anterior of the T9−T10 vertebral region of the abdomen. Cardioprotection after NIC requires the integrity of the spinal cord from the region of stimulation to the thoracic vertebral region of the origin of the cardiac nerves but does not require that the cord be intact in the cervical region. Thus, we show that NIC is a reflex and not a central nervous system-mediated effect. The mechanism involves bradykinin 2 receptor activity and activation of PKC, specifically, PKC-α. The similarity of the neuroanatomy and conservation of the effectors of cardioprotection supports that NIC may be translatable to humans as a nontraumatic and practical adjunct therapy against ischemic disease. NEW & NOTEWORTHY This study shows that an electrical stimulus to skin sensory nerves elicits a very powerful cardioprotection against myocardial infarction. This stimulus works by a neurogenic mechanism similar to that previously elucidated for remote cardioprotection of trauma. Nociceptor-induced conditioning is equally potent when applied before ischemia or at reperfusion and has great potential clinically.

TRPV1 Supports Axogenic Enhanced Excitability in Response to Neurodegenerative Stress

“…Adult male Trpv1 −/− (B6.129× 1-Trpv1 tm1Jul /J) mice (1.5–2 months old, n = 18) were obtained from The Jackson Laboratory (Bar Harbor, ME, USA), while the appropriate WT background strain C57Bl/6 mice were purchased from Charles River Laboratories (male, 1.5–2 months old, n = 18, Wilmington, MA, USA). The Trpv1 −/− mice have a targeted mutation causing a non-functional truncated form of TRPV1 (Caterina et al, 2000 ; Ren et al, 2019 ; Stanford et al, 2019 ). Mice were maintained in 12 h light/dark cycles, and animals were allowed water and standard rodent chow as desired.…”

TRPV1 Tunes Optic Nerve Axon Excitability in Glaucoma

“…The mutant forward primer was TAA AGC GCA TGC TCC AGA CT compared with the WT forward primer of TGG CTC ATA TTT GCC TTC AG. The common primer was CAG CCC TAG GAG TTG ATG GA. DNA gel electrophoresis of Trpv1 −/− animals showed a single band at 176 bp, indicative of truncated TRPV1 (Caterina et al, 2000;Ren et al, 2019;Stanford et al, 2019), whereas WT showed a single band at 289 bp indicative of the native protein. We verified this pattern in each animal utilized.…”

“…Adult male Trpv1 −/− (B6.129 × 1-Trpv1 TM1Jul /J) mice (1.5-2 months old) were obtained from The Jackson Laboratory, whereas the appropriate wild-type (WT) background strain C57Bl/6 mice were purchased from Charles River Laboratories (male, 1.5-2 months old). The Trpv1 −/− mice have a targeted mutation causing a non-functional truncated form of TRPV1 (Caterina et al, 2000;Ren et al, 2019;Stanford et al, 2019). Trpv1 −/− animals were genotyped prior to performing experiments, following our protocol (Ward et al, 2014;Weitlauf et al, 2014;Sappington et al, 2015) using primers recommended by the vendor.…”

“…Following our protocol for conformational genotyping (Ward et al, 2014;Weitlauf et al, 2014;Sappington et al, 2015), Trpv1 −/− mice showed a single product band at 176 bp, indicative of a non-functional truncated form of Trpv1 (Caterina et al, 2000;Ren et al, 2019;Stanford et al, 2019), whereas WT C57 mice had a prominent band at 289 bp characteristic of the native protein ( Figure 1A).…”

Proteomic and metabolomic characterization of cardiac tissue in acute myocardial ischemia injury rats

“…Moreover, pathway analysis showed that the altered metabolites and proteins were related to neuroactive ligand-receptor interaction. Previous research indicated that the nervous system, including the sympathetic system and the parasympathetic system, regulates cardiac activity regardless of the heart's physiological condition [43,44]. In addition, researchers have reported that the cardio protection effects of sevoflurane is associated with neuroactive ligandreceptor interaction in patients undergoing coronary artery bypass graft surgery [45].…”