Ceramide Changes the Mediator of Flow-Induced Vasodilation from Nitric Oxide to Hydrogen Peroxide in the Human Microcirculation
Rationale: Mitochondrial-derived hydrogen peroxide (H2O2) regulates flow-induced dilation (FID) in microvessels from patients with coronary artery disease (CAD). The relationship between ceramide, an independent risk factor for CAD and a known inducer of mitochondrial reactive oxygen species (ROS), and FID is unknown.
Objective: We examined the hypothesis that exogenous ceramide induces a switch in the mediator of FID from nitric oxide (NO) to H2O2.
Methods and Results: Internal diameter changes of resistance arterioles from human adipose and atrial tissue were measured by videomicroscopy. Mitochondrial H2O2 production was assayed in arterioles using MitoPeroxy Yellow 1 (Mito PY1). PEG-catalase, rotenone, and Mito-TEMPO, impaired FID in healthy adipose arterioles pre-treated with ceramide whereas Nω-Nitro-L-arginine methyl ester (L-NAME) had no effect. Mitochondrial H2O2 production was induced in response to flow in healthy adipose vessels pre-treated with ceramide and this was abolished in the presence of PEG-catalase. Immunohistochemistry demonstrated ceramide accumulation in arterioles from both healthy and CAD patients. L-NAME reduced vasodilation to flow in adipose as well as atrial vessels from patients with CAD incubated with GW4869, a neutral sphingomyelinase (NSmase) inhibitor, whereas PEG-catalase had no effect.
Conclusions: Our data indicate that ceramide has an integral role in the transition of the mediator of FID from NO to mitochondrial-derived H2O2 and that inhibition of ceramide production can revert the mechanism of dilation back to NO. Ceramide may be an important target for preventing and treating vascular dysfunction associated with atherosclerosis.
- nitric oxide
- reactive oxygen species
- endothelial dysfunction
- shear stress
- Received March 4, 2014.
- Revision received June 10, 2014.
- Accepted June 11, 2014.