Differential regulation of TRPV1 channels in the murine coronary vasculature by H2O2.

摘要

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 H2O 2 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 H2O 2 - 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.