Abstract 298: Cytochrome P4501A1 Contributes to Nitric Oxide-Dependent Vasodilation and Blood Pressure Lowering on an Omega-3 Polyunsaturated Fatty Acid-Enriched Diet

Abstract

Cytochrome P4501A1 (CYP1A1) stereospecifically metabolizes omega-3 polyunsaturated fatty acids (n-3 PUFA) to potent vasodilators in vitro. We have previously reported that CYP1A1 knockout (KO) mice are hypertensive and exhibit significantly reduced vasodilatory responses to the n-3 PUFAs, eicosapentaenoic and docosahexaenoic acids. We next tested the hypothesis that CYP1A1 KO mice would exhibit significantly different vascular and blood pressure responses to diets enriched in n-3 versus n-6 PUFAs. CYP1A1 wildtype (WT) and KO mice were fed normal chow or diets enriched in either n-3 or n-6 PUFAs for 2 mo, and then blood pressure was assessed by radiotelemetry ± nitric oxide synthase (NOS) inhibitor (NG-nitro-L-Arginine). Acetylcholine (Ach)-mediated vasodilation was assessed in first order mesenteric arteries, and endothelial NOS and phospho-eNOS were measured in the aorta. We found that an n-3 enriched diet significantly reduced mean arterial pressure (MAP) in CYP1A1 KO mice (Chow: 116.0 ± 1.2; n-3 diet: 107.6 ± 1.5, p<0.05) with no effect in WT mice (Chow: 103.0 ± 0.9; n-3 diet: 105.0 ± 2.5). In contrast, an n-6 enriched diet significantly increased MAP in WT mice (Chow: 103.0 ± 0.9; n-6: 118.2 ± 4.1, p<0.05) with no effect in KO mice (Chow: 116.0 ± 1.2; n-6: 115.3 ± 1.5). Interestingly, NOS inhibition increased blood pressure significantly more in the CYP1A1 WT mice (+16 ± 0.5 mmHg) than KO mice (+11 ± 0.6, p<0.002) on an n-3 diet, but resulted in similar increases in blood pressure in both genotypes on an n-6 diet (WT: +11 ± 1.8; KO: +11 ± 0.8). In addition, CYP1A1 KO mice on an n-3 enriched diet exhibited significantly reduced Ach-dependent dilation in mesenteric arteries and reduced expression of aortic phospho-eNOS, compared to WT. However, neither of these endpoints were altered in KO mice on an n-6 diet, compared to WT. Taken together, these data suggest that CYP1A1 contributes to the NO-mediated vasodilation and blood pressure lowering benefits derived from dietary n-3 PUFAs.