Role of CYP4A/20‐HETE Pathway in Vascular Oxidative Stress in the Dahl Salt‐Sensitive Rat

Abstract

We tested the hypothesis that cytochrome P450‐4A (CYP4A) and 20‐hydroxyeicosatetraenoic acid (20‐HETE) contribute to vascular oxidant stress and endothelial dysfunction in Dahl salt‐sensitive (SS) rats. Endothelial dysfunction in SS rats was ameliorated by a CYP4A inhibitor (DDMS) or a 20‐HETE antagonist (20‐HEDE), and in SS‐5BN consomic rats carrying CYP4A genes from the Brown Norway rat on the SS genetic background. Superoxide (SOX) levels, assessed via DHE fluorescence, were significantly higher in cerebral arteries of SS rats vs. SS‐5BN rats fed either normal salt (NS, 0.4% NaCl) or high salt (HS, 4.0% NaCl) diet. DDMS reduced SOX in arteries of HS‐fed SS rats to the same degree as a superoxide scavenger (PEG‐SOD), suggesting that the CYP4A/20‐HETE system contributes to elevated vascular SOX in HS‐fed SS rats. CYP4A protein expression was significantly higher in cerebral arteries of SS rats fed NS or HS diet vs. SS‐5BN rats. CuZn SOD, MnSOD, and EC‐SOD expression was similar in SS vs. SS‐5BN, indicating that the elevated vascular SOX in SS vs. SS‐5BN rats is not due to differences in antioxidant defenses. Treatment with the superoxide scavenger tempol had no effect on CYP4A expression in either strain. These findings indicate that increased expression/activity of the CYP4A/20‐HETE system contributes to vascular oxidant stress and endothelial dysfunction in SS rats fed either NS or HS diet. [NIH #HL65289, HL72920, HL92026, and AHA].