Abstract 150: Oscillatory Shear Stress Promotes Nitrative Stress Relative to Pulsatile Shear Stress: A Potential Mechanism for Athero-Prone Regions within Vascular Bifurcations
Fluid shear stress is involved in the development of the focal nature of atherosclerosis. In this study, the contribution of oxidative and nitrative stress was examined in models of oscillatory shear stress (OSS: occurring at the lateral wall of arterial bifurcations) and pulsatile shear stress (PSS: occurring at the medial wall of bifurcations or straight regions). Immunostaining of human coronary arteries revealed nitrotyrosine in the OSS-exposed regions and eNOS in the PSS-exposed regions. Bovine aortic endothelial cells (BAEC) were exposed to shear stress conditions that simulated human arterial flow:
PSS at a mean shear stress (τave) of 23 dyn·cm−2 and a temporal gradient (dτ/dt) at 71 dyn×cm−2sec−1 and
OSS at tave= 0.02 dyn×cm−2 and dt/dt = ± 3.0 dyn×cm−2×s−1 at a frequency of 1 Hz. OSS significantly up-regulated NADPH oxidase (Nox4) expression, accompanied by superoxide anion (O2−·) production higher than that elicited by PSS.
Conversely, the level of NO production elicited by PSS (total NO2− and NO3−) was higher than that triggered by OSS. LDL protein modifications elicited by shear stress were assessed in this experimental model by liquid chromatography and tandem mass spectrometry (LC/MS/MS): OSS induced a higher level of LDL Apo B 100 nitration and oxidation than did PSS. The levels of di-tyrosine and o-hydroxy-phenylalanine (o-Phe) in LDL apoB-100 were significantly higher than those of 3-nitrotyrosine, thus indicating a prevalence of oxidation over nitration: [o-Phe] > [di-Tyr] >> [NO2-Tyr]. LC/MS/MS analyses of modified LDL in response to ONOO- treatment revealed nitration of tyrosine residues at a and b helices: alpha-1 (Tyr144), alpha-2 (Tyr2524), beta-2 (Tyr3295), aalpha-3 (Tyr4116), and beta-2 (Tyr4211). These observations suggest that oscillatory shear stress contributes to an imbalance in the production of O2−· and ·NO, hence leading to an enhanced oxidative and nitrative stress in the athero-prone regions within vascular bifurcations.