The p38/mitogen-activated protein (MAP) kinase-activated protein kinase 2 (MAPKAP kinase 2)/heat shock protein (HSP)25/27 pathway is thought to play a critical role in actin dynamics. In the present study, we examined whether p38 was involved in the morphological changes seen in endothelial cells (EC) exposed to shear stress. Cultured bovine aortic EC were subjected to 14 dyn/cm(2) laminar steady shear stress. Peak activation of p38, MAPKAP kinase 2, and HSP25 were sixfold at 5 min, sixfold at 5 min, and threefold at 30 min compared with static control, respectively. SB-203580 (1 microM), a specific inhibitor of p38, abolished the activation of MAPKAP kinase 2 and HSP25 as well as EC elongation and alignment in the direction of flow elicited by shear stress. The mean orientation angle of cells subjected to shear without SB-203580, with SB-203580, or static control were 17, 50, and 43 degrees, respectively (P < 0. 05). EC transfected with the dominant negative mutant of p38-alpha aligned randomly with no stress fiber formation despite exposure to shear stress. These data suggests that the pathway of p38/MAPKAP kinase 2/HSP25/27 is activated in response to shear stress, and this pathway plays an important role in morphological changes induced by shear stress.

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA-reductase) inhibitors, otherwise known as statins, are currently the medical treatment of choice for hypercholesterolemia. Hypercholesterolemia is a known risk factor for cardiovascular disease, and statin therapy has led to a significant reduction in morbidity and mortality from adverse cardiac events, stroke, and peripheral arterial disease. In addition to achieving a therapeutic decrease in serum cholesterol levels, statin therapy appears to promote other effects that are independent of changes in serum cholesterol. These ''pleiotropic'' effects include attenuation of vascular inflammation, improved endothelial cell function, stabilization of atherosclerotic plaque, decreased vascular smooth muscle cell migration and proliferation, and inhibition of platelet aggregation. This article is part I of a 2-part review, and it focuses on the pleiotropic effects of statins at the cellular level.

therosclerosis is a chronic disease attributed to risk factors that are systemic in nature. Yet the lesions involved do not occur in random fashion. The coronary arteries, the major branches of the aortic arch, and the abdominal aorta and its visceral and major lower extremity branches are particularly susceptible sites. Hemodynamic forces interacting with an active vascular endothelium are responsible for localizing lesions in a nonrandom pattern of distribution. Shear stress and cyclic circumferential strain are the predominant forces that have been characterized. The modification of endothelial cell structure and function by these mechanical forces sheds insight into the vasculature's propensity for atherogenesis.

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