Differential regulation of TRPV1 channels by H2O2: implications for diabetic microvascular dysfunction

Daniel J. DelloStritto, Patrick J. Connell, Gregory M. Dick, Ibra S. Fancher, Brittany Klarich, Joseph N. Fahmy, Patrick T. Kang, Yeong Renn Chen, Derek S. Damron, Charles K. Thodeti, Ian N. Bratz

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19 Scopus citations

Abstract

We demonstrated previously that TRPV1-dependent coupling of coronary blood flow (CBF) to metabolism is disrupted in diabetes. A critical amount of H2O2 contributes to CBF regulation; however, excessive H2O2 impairs responses. We sought to determine the extent to which differential regulation of TRPV1 by H2O2 modulates CBF and vascular reactivity in diabetes. We used contrast echocardiography to study TRPV1 knockout (V1KO), db/db diabetic, and wild type C57BKS/J (WT) mice. H2O2 dose-dependently increased CBF in WT mice, a response blocked by the TRPV1 antagonist SB366791. H2O2-induced vasodilation was significantly inhibited in db/db and V1KO mice. H2O2 caused robust SB366791-sensitive dilation in WT coronary microvessels; however, this response was attenuated in vessels from db/db and V1KO mice, suggesting H2O2-induced vasodilation occurs, in part, via TRPV1. Acute H2O2 exposure potentiated capsaicin-induced CBF responses and capsaicin-mediated vasodilation in WT mice, whereas prolonged luminal H2O2 exposure blunted capsaicin-induced vasodilation. Electrophysiology studies re-confirms acute H2O2 exposure activated TRPV1 in HEK293A and bovine aortic endothelial cells while establishing that H2O2 potentiate capsaicin-activated TRPV1 currents, whereas prolonged H2O2 exposure attenuated TRPV1 currents. Verification of H2O2-mediated activation of intrinsic TRPV1 specific currents were found in isolated mouse coronary endothelial cells from WT mice and decreased in endothelial cells from V1KO mice. These data suggest prolonged H2O2 exposure impairs TRPV1-dependent coronary vascular signaling. This may contribute to microvascular dysfunction and tissue perfusion deficits characteristic of diabetes.

Original languageEnglish
Article number21
Pages (from-to)1-16
Number of pages16
JournalBasic Research in Cardiology
Volume111
Issue number2
DOIs
StatePublished - 1 Mar 2016

Keywords

  • Capsaicin
  • Coronary blood flow
  • Hydrogen peroxide
  • Reactive oxygen species
  • TRPV1

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    DelloStritto, D. J., Connell, P. J., Dick, G. M., Fancher, I. S., Klarich, B., Fahmy, J. N., Kang, P. T., Chen, Y. R., Damron, D. S., Thodeti, C. K., & Bratz, I. N. (2016). Differential regulation of TRPV1 channels by H2O2: implications for diabetic microvascular dysfunction. Basic Research in Cardiology, 111(2), 1-16. [21]. https://doi.org/10.1007/s00395-016-0539-4