Differential Regulation of TRPV1 Channels in the Murine Coronary Vasculature by H2O2
Institution: | Kent State University |
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Department: | College of Arts and Sciences / School of Biomedical Sciences |
Degree: | MS |
Year: | 2014 |
Keywords: | Biomedical Research; TRPV1, 4-HNE, Reactive Oxygen Species, H2O2, Cardiovascular disease, Diabetic cardiomyopathy, Oxidative Stress, Microvascular Disease |
Record ID: | 2045450 |
Full text PDF: | http://rave.ohiolink.edu/etdc/view?acc_num=kent1398336723 |
A critical amount of reactive oxygen species (ROS) contributes to coronary blood flow (CBF) regulation; however, oxidative stress (OS) impairs CBF regulation and is elevated in diabetes. We have previously demonstrated TRPV1- dependent coupling of CBF to metabolism is disrupted in diabetic cardiomyopathy (DCM). Accordingly, we hypothesized that basal levels of H2O2 stimulate TRPV1 whereas enhanced oxidative stress desensitizes and/or deactivates TRPV1 indirectly via a mechanism involving the lipid peroxidation product 4-Hydroxy-2-nonenal (4-HNE). H2O2 caused robust dilation in control coronary microvessels (blunted in the presence of the TRPV1 inhibitor SB366791 and in TRPV1-/- vessels), suggesting H2O2 - induced vasodilation occurs in part via TRPV1. Acute exposure to H2O2 potentiates capsaicin – mediated (TRPV1 agonist) vasodilation while a prolonged exposure to H2O2 eliminates this TRPV1 – dependent response. Interestingly, coronary microvessels isolated from db/db mice exhibit diminished H2O2 – induced coronary dilation when compared to controls remaining consistent with our previous findings. Lastly, coronary microvessels isolated from control mice incubated with 4-HNE demonstrate reduced TRPV1 – dependent coronary vasoreactivity. These data suggest low levels of H2O2 can potentiate TRPV1 activation. However, increased ROS concentrations, as seen in DCM, can lead to enhanced 4-HNE levels which modulate TRPV1 and disrupt its signaling. Thus, H2O2 – mediated differential regulation of TRPV1 could provide insight into the mechanism responsible for the uncoupling of myocardial blood flow (MBF) to metabolism associated with diabetes and DCM.