Mechanical Stretch Induces Phosphorylation of p38-MAPK and Apoptosis in Human Saphenous Vein

Abstract

Objective-Failure of saphenous vein grafts remains a major limitation of coronary bypass surgery. The aims of the present study were to determine whether pressure distension of human saphenous vein induces the activation of p38-MAPK and to determine its role in apoptosis. Methods and Results-Phosphorylated p38 was detected at basal levels in human saphenous vein obtained immediately after harvesting. Distended saphenous vein showed significantly higher levels of phosphorylated p38 compared with control vein (PϽ0.01) and nondistended saphenous vein maintained for 3 and 6 hours after harvesting (both PϽ0.01 A utologous saphenous vein (SV) is the commonest conduit used for peripheral and coronary artery bypass grafting. However, 30% to 50% of vein grafts become occluded by 10 years. 1 The causes of vein graft occlusion are thrombosis in the early stages, and later the proliferation and migration of intimal smooth muscle cells along with the deposition of extracellular matrix leading to myointimal hyperplasia. 1 The precise cellular mechanisms involved in these processes remain unclear; however, surgical trauma to the vessel, including the stretch that occurs during manual distension before implantation, as well as implantation of the vein into the arterial circulation may be important.Apoptosis is reported to occur in pathological SV grafts, where it is thought to be involved in the transformation of a smooth muscle cell-rich myointimal thickening toward a fibrous cell-poor intimal thickening. 2,3 Apoptosis has also been shown to occur in tissue remodeling, associated with longitudinal stretch (axial strain) in rabbit carotid arteries. 4 We have previously shown that apoptosis is induced in pressure-distended human SV and is associated with increased vessel wall expression of the transcription factor c-fos, a downstream component of various signaling cascades. 5 In cultured porcine vascular smooth muscle cells (VSMCs), cyclic stretch has been shown to cause an increase in apoptosis, accompanied by a sustained activation of the mitogen-activated protein kinases (MAPK) JNK and p38. 6 In vitro studies using cultured smooth muscle cells have shown that mechanical stretch can activate ras/rac/p38 signal pathways 7 and p38 phosphorylates p53, which is responsible for mechanical stress-induced apoptosis. 8 In addition, the application of biomechanical stress has been shown to increase apoptosis in mouse vein grafts, and this occurs via p38 activation. 9 MAPKs are proline-directed serine/threonine kinases activated by dual phosphorylation on threonine and tyrosine residues in response to a wide variety of extracellular stimuli. The JNK and p38 MAPK signaling cascades are activated in response to cellular stress and certain cytokines via the activation of G protein coupled receptors 10 and are known to be involved in apoptosis. 11 Overexpression of MAPKs upstream of p38, such as MKK-3, leads to sustained activation of p38 and apoptosis. 12,13 However, ERK-MAPK is downregulated during apoptosis and upregulated during cellula...

Dexamethasone Arterializes Venous Endothelial Cells by Inducing Mitogen-Activated Protein Kinase Phosphatase-1

“…Our findings are particularly relevant to grafting of veins into the arterial circulation, a procedure that exposes veins to new forces that can cause EC injury or activation. Stretching of veins during harvesting and preparation for grafting can lead to partial loss of ECs, 34 whereas a "no touch" technique for vein harvest leads to the preservation of ECs. 35,36 Veins grafted into the arterial circulation are also exposed to a sudden increase in blood flow, which elevates shear stress at the vascular wall.…”

Proteomic and Metabolomic Analysis of Vascular Smooth Muscle Cells

“…26,27 These findings were subsequently confirmed by others. [42][43][44] Importantly, enhanced apoptosis after mechanical injury is associated with a decrease in GSH levels, 45 and the response of SMCs to mechanical strain is modulated by glucose 6-phosphate dehydrogenase activity. 23 Therefore, our mechanistic data provide a better explanation of why PKC␦ Ϫ/Ϫ SMCs are resistant to apoptosis and contribute to accelerated neointima formation in PKC␦ Ϫ/Ϫ vein grafts.…”

Impaired Fibrillin-1 Function Promotes Features of Plaque Instability in Apolipoprotein E–Deficient Mice

“…24 Several studies have shown that increased cyclic strain induces apoptosis of SMCs. 25,26 The SMC response to cyclic strain is determined by the phenotype, with growth inhibition in the synthetic SMC phenotype as opposed to increased proliferation in the contractile SMC phenotype. 27 In this regard, it should be noted that one of the first detectable alterations in Marfan mice is the loss of the connecting filaments, which are composed of microfibrils and connect SMCs to the elastic lamellae.…”