Flow shear stress and atherosclerosis: a matter of site specificity

• Published in: Antioxidants & redox signaling Vol. 15; no. 5; p. 1405
• Main Authors: Nigro, Patrizia, Abe, Jun-Ichi, Berk, Bradford C
• Format: Journal Article
• Language: English
• Published: United States 01.09.2011
• Subjects: Animals; Atherosclerosis - genetics; Atherosclerosis - metabolism; Endothelial Cells - metabolism; Gene Expression Regulation; Hemodynamics - physiology; Humans; Phenotype; Protein Kinase C - metabolism; Reactive Oxygen Species - metabolism; Shear Strength; Signal Transduction - physiology; Stress, Mechanical
• ISSN: 1557-7716
• DOI: 10.1089/ars.2010.3679

It is well accepted that atherosclerosis occurs in a site-specific manner especially at branch points where disturbed blood flow (d-flow) predisposes to the development of plaques. Investigations both in vivo and in vitro have shown that d-flow is pro-atherogenic by promoting oxidative and inflammatory states in the artery wall. In contrast, steady laminar blood flow (s-flow) is atheroprotective by inhibition of oxidative stress and inflammation in the vessel wall. The mechanism for inflammation in endothelial cells (ECs) exposed to d-flow has been well studied and includes redox-dependent activation of apoptosis signal-regulating kinase 1 (ASK1) and Jun NH2-terminal kinase (JNK) that ultimately lead to the expression of adhesive molecules. In contrast, s-flow leads to the activation of the mitogen extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) pathway that prevents pro-inflammatory signaling. Important transcriptional events that reflect the pro-oxidant and pro-inflammatory condition of ECs in d-flow include the activation of activator protein 1 (AP-1) and nuclear factor kappaB (NFκB), whereas in s-flow, activation of Krüppel-like factor 2 (KLF2) and nuclear factor erythroid 2-like 2 (Nrf2) are dominant. Recent studies have shown that protein kinase c zeta (PKCζ) is highly activated under d-flow conditions and may represent a molecular switch for EC signaling and gene expression. The targeted modulation of proteins activated in a site-specific manner holds the promise for a new approach to limit atherosclerosis.