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

Xiaoping Ren, Anne E. Roessler, Thomas L. Lynch, Lauren Haar, Faryal Mallick, Yong Lui, Michael Tranter, Michelle Huan Ren, Wen Rui Xie, Guo Chang Fan, Jun Ming Zhang, Evangelia G. Kranias, Ahmad Anjak, Sheryl Koch, Min Jiang, Qing Miao, Yang Wang, Albert Cohen, Jack Rubinstein, Neal Lee WeintraubW. Keith Jones

Research output: Contribution to journalArticle

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 and 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.

Original languageEnglish (US)
Pages (from-to)H543-H553
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume316
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Nociceptors
Skin
Reperfusion
Myocardial Infarction
Bradykinin Receptors
Spinal Cord Stimulation
Umbilicus
Neuroanatomy
Unmyelinated Nerve Fibers
Conditioning (Psychology)
Capsaicin
Peripheral Nerves
Abdomen
Infarction
Reflex
Thorax
Ischemia
Central Nervous System
Heart Failure
Morbidity

Keywords

  • Cardioprotection
  • Nociceptor-induced conditioning
  • Remote conditioning
  • Remote preconditioning of trauma

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Cardioprotection via the skin : Nociceptor-induced conditioning against cardiac MI in the NIC of time. / Ren, Xiaoping; Roessler, Anne E.; Lynch, Thomas L.; Haar, Lauren; Mallick, Faryal; Lui, Yong; Tranter, Michael; Ren, Michelle Huan; Xie, Wen Rui; Fan, Guo Chang; Zhang, Jun Ming; Kranias, Evangelia G.; Anjak, Ahmad; Koch, Sheryl; Jiang, Min; Miao, Qing; Wang, Yang; Cohen, Albert; Rubinstein, Jack; Weintraub, Neal Lee; Jones, W. Keith.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 316, No. 3, 01.03.2019, p. H543-H553.

Research output: Contribution to journalArticle

Ren, X, Roessler, AE, Lynch, TL, Haar, L, Mallick, F, Lui, Y, Tranter, M, Ren, MH, Xie, WR, Fan, GC, Zhang, JM, Kranias, EG, Anjak, A, Koch, S, Jiang, M, Miao, Q, Wang, Y, Cohen, A, Rubinstein, J, Weintraub, NL & Jones, WK 2019, 'Cardioprotection via the skin: Nociceptor-induced conditioning against cardiac MI in the NIC of time', American Journal of Physiology - Heart and Circulatory Physiology, vol. 316, no. 3, pp. H543-H553. https://doi.org/10.1152/ajpheart.00094.2018
Ren, Xiaoping ; Roessler, Anne E. ; Lynch, Thomas L. ; Haar, Lauren ; Mallick, Faryal ; Lui, Yong ; Tranter, Michael ; Ren, Michelle Huan ; Xie, Wen Rui ; Fan, Guo Chang ; Zhang, Jun Ming ; Kranias, Evangelia G. ; Anjak, Ahmad ; Koch, Sheryl ; Jiang, Min ; Miao, Qing ; Wang, Yang ; Cohen, Albert ; Rubinstein, Jack ; Weintraub, Neal Lee ; Jones, W. Keith. / Cardioprotection via the skin : Nociceptor-induced conditioning against cardiac MI in the NIC of time. In: American Journal of Physiology - Heart and Circulatory Physiology. 2019 ; Vol. 316, No. 3. pp. H543-H553.
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AU - Haar, Lauren

AU - Mallick, Faryal

AU - Lui, Yong

AU - Tranter, Michael

AU - Ren, Michelle Huan

AU - Xie, Wen Rui

AU - Fan, Guo Chang

AU - Zhang, Jun Ming

AU - Kranias, Evangelia G.

AU - Anjak, Ahmad

AU - Koch, Sheryl

AU - Jiang, Min

AU - Miao, Qing

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N2 - 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 and 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.

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