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  • br Introduction Cardiovascular disease continues to be the l

    2021-07-20


    Introduction Cardiovascular disease continues to be the leading cause of death in developed countries. Atherosclerosis, a chronic inflammatory cardiovascular disease, is characterized by the progressive buildup of oxidized low density lipoproteins in the arterial walls (Ross, 1999). In the development of atherosclerosis, local endothelial cell dysfunction leads to inflammatory response cascades and the accumulation of low-density lipoprotein (LDL) within the artery walls. Endothelium disruption causes increased inflammatory response and the infiltration of LDL, cholesterol, and fats into the sub-endothelial space (Maton, 1993). When LDLs become trapped in the wall, they become oxidized, and oxidized LDLs (ox-LDLs) lead to the recruitment of monocytes and other inflammatory response molecules to the entrapment site. The ox-LDLs lose recognition of their receptors and bind to receptors non-specifically, resulting in leaky vessel wall. Monocytes develop into macrophages which, with continued lipid uptake, develop further into foam cells. With the infiltration of smooth muscle tie2 (SMC), fibrous connective tissue form over the inflammation site. These arterial lesions develop into an atherosclerotic plaque that could result in an acute thrombotic event (Berliner et al., 1995, Glaudemans et al., 2010). Proper endothelial functions are vital in maintaining vascular wall integrity and cellular homeostasis, while endothelial dysfunction can lead to pathological conditions such as atherosclerosis or cancer (Arab et al., 2008). The endothelial cells (EC) are constantly exposed to hemodynamic forces of blood flow which exerts both normal pressure and tangential shear stress on the endothelium. Interestingly, atherosclerotic plaque tends to occur near bifurcation sites with disturbed flow, where endothelial cells display a pro-atherosclerotic phenotype. On the other hand, straight sections with uniform, laminar flow tend to remain healthy, regardless of other health factors or lifestyle choices (Gimbrone et al., 1997, Li et al., 2005). The local hemodynamic profile is a key determinant of EC molecular expression, cell morphology, and overall function (Garcia-Cardena et al., 2001). ECs respond to both mechanical and biochemical stimuli in their environment via signaling transduction mechanism that involve mitogen-activated protein kinases (MAPKs) and myriad of transcription factors. Apoptosis is a highly regulated cell death process important in maintaining vascular wall integrity. The loss of apoptotic regulation is often associated with various disease mechanisms such as in cancer. Excessive endothelial cell turnover and apoptosis in athero-susceptible regions creates leaky wall, disrupts the endothelium barrier and initiates inflammatory signals, allowing for ox-LDL accumulation. In fact, the lack of mechanical stimuli has been shown to trigger apoptosis in endothelial cells, highlighting the crucial role of hemodynamic forces in maintaining vascular wall integrity (Kaiser et al., 1997). Due to the important role of apoptosis in multiple cellular processes, its activation and regulation present an interesting avenue of research. Identifying key apoptosis signals in response to shear stress will further advance our understanding of atherosclerosis development and progression in the endothelium. Death-associated protein kinase (DAPK), a known apoptosis regulator, is shown to be up-regulated in atherosclerotic lesions (Arab et al., 2008). DAPK up-regulation leads to increased cell turnover and arterial wall instability, which provides increase susceptibility to LDL absorption (Schumacher et al., 2002). In cancer pathology, DAPK expression is silenced in some forms of cancer (Cohen and Kimchi, 2001); and the tumor suppression ability of DAPK has been demonstrated: both as inhibitor of metastasis in vivo (Cohen et al., 1999) and as an apoptotic promoter in vitro (Pelled et al., 2002). Aside with its apoptosis activity, DAPK also binds to and regulates actin in the cytoskeleton (Bialik et al., 2004, Shohat et al., 2001). In endothelial cells, tropomyosin-1, another subject of DAPK phosphorylation, is important in maintaining cardiovascular homeostasis and its expression is lost in tumor cells (Bharadwaj et al., 2005). Understanding endothelial DAPK expression and function will help elucidate overlaps between the apoptotic and shear stress signaling pathways. This review will assess our current knowledge on the effect of shear stress on endothelial cell phenotype, apoptosis, and DAPK. Fluid shear stress may regulate DAPK signaling for both pro- and anti-apoptotic processes, and we evaluate the potential role of DAPK in endothelial mechanotransduction and apoptosis in the vasculature.