title: Differential regulation of TRPV1 channels by H2O2: implications for diabetic microvascular dysfunction.
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.
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DelloStritto
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Connell
authors.affiliation: California Medical Innovations Institute, San Diego, CA, 92121, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Dick
authors.affiliation: Department of Physical Therapy, University of Illinois at Chicago, Chicago, IL, 60607, USA.
authors.forename: Ibra S
authors.initials: IS
authors.lastname: Fancher
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Klarich
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Fahmy
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Kang
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Yeong-Renn
authors.initials: YR
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, Kent State University, Kent, OH, 44240, USA.
authors.forename: Derek S
authors.initials: DS
authors.lastname: Damron
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Charles K
authors.initials: CK
authors.lastname: Thodeti
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA. ibratz@neomed.edu.
authors.forename: Ian N
authors.identifier: http://orcid.org/0000-0002-6484-9631
authors.initials: IN
authors.lastname: Bratz
mesh_terms: D000818:Animals; D003326:Coronary Circulation; D003925:Diabetic Angiopathies / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D050916:TRPV Cation Channels; D006861:Hydrogen Peroxide
keywords: Capsaicin; Coronary blood flow; Hydrogen peroxide; Reactive oxygen species; TRPV1