Role of vascular reactive oxygen species in regulating cytochrome P450-4A enzyme expression in Dahl salt-sensitive rats

Objective: The potential contribution of CYP4A enzymes to endothelial dysfunction in Dahl salt-sensitive rats was determined by comparison to SS-5^BN consomic rats having chromosome 5 carrying CYP4A alleles from the BN rat introgressed into the SS genetic background. Methods: The following experiments were performed in cerebral arteries from HS-fed SS and SS-5^BN rats ± the SOD inhibitor DETC and/or the superoxide scavenger Tempol: (i) endothelial function was determined via video microscopy ± acute addition of the CYP4A inhibitor DDMS or Tempol; (ii) vascular oxidative stress was assessed with DHE fluorescence ± acute addition of DDMS, l-NAME, or PEG-SOD; and (iii) CYP4A protein levels were compared by western blotting. Results: In DETC-treated SS-5^BN and HS-fed SS rats, (i) DDMS or Tempol ameliorated vascular dysfunction, (ii) DDMS reduced vascular oxidative stress to control levels, (iii) chronic Tempol treatment reduced vascular CYP4A protein expression, and (iv) combined treatment with Tempol and l-NAME prevented the reduction in CYP4A protein expression in MCA of HS-fed SS rats. Conclusion: The CYP4A pathway plays a role in vascular dysfunction in SS rats and there appears to be a direct role of reduced NO availability due to salt-induced oxidant stress in upregulating CYP4A enzyme expression.