Vascular endothelial cells (ECs) are exposed to different patterns of blood flow (disturbed vs. laminar) and the associated shear stresses (oscillatory [OSS] vs. pulsatile [PSS]), which lead to differential EC responses. We investigated the roles of classes I and II histone deacetylases (HDACs, i.e., HDAC-1/2/3 and HDAC-5/7, respectively) in regulating NF-E2-related factor-2 (Nrf2) and Kr?ppel-like factor-2 (KLF2), two important transcription factors that govern many shear-responsive genes, and cell cycle in ECs in response to OSS. Application of OSS (0.5?4 dynes/cm2) to ECs up-regulated both classes I and II HDACs and their nuclear accumulations, whereas PSS (12?4 dynes/cm2) induced phosphorylation-dependent nuclear export of class II HDACs. OSS induced the association of HDAC-1/2/3 with Nrf2 and HDAC-3/5/7 with myocyte enhancer factor-2, and the deacetylations of these HDACs led to down-regulations of the antioxidant gene NAD(P)H quinone oxidoreductase-1 (NQO1) and KLF2 in ECs. Transfecting ECs with HDAC-1/2/3- and HDAC-3/5/7-specific small interfering RNAs eliminated the OSS-induced down-regulations of NQO1 and KLF2, respectively. OSS up-regulated cyclin A and phospho-retinoblastoma and down-regulated p21CIP1 in ECs and hence their proliferation; these effects are mediated by HDAC-1/2/3. The OSS-induced HDAC signaling and EC responses are mediated by phosphatidylinositol 3-kinase/Akt. Immunohistochemical examinations of the experimentally stenosed rat abdominal aorta showed high levels of HDAC-2/3/5 in the EC layer at post-stenotic sites, where OSS occurs. Our findings indicate the importance of different HDACs in regulating endothelial oxidative, inflammatory, and proliferative responses to disturbed flow with OSS.
