Adaptor Protein p66Shc Mediates Hypertension-Associated, Cyclic Stretch-Dependent, Endothelial Damage [Endothelium]

Increased cyclic stretch to the vessel wall, as observed in hypertension, leads to endothelial dysfunction through increased free radical production and reduced nitric oxide bioavailability. Genetic deletion of the adaptor protein p66Shc protects mice against age-related and hyperglycemia-induced endothelial dysfunction, as well as atherosclerosis and stroke. Furthermore, p66Shc mediates vascular dysfunction in hypertensive mice. However, the direct role of p66Shc in mediating mechanical force–induced free radical production is unknown; thus, we studied the effect of cyclic stretch on p66Shc activation in primary human aortic endothelial cells and aortic endothelial cells isolated from normotensive and hypertensive rats. Exposure of human aortic endothelial cells to cyclic stretch led to a stretch- and time-dependent p66Shc phosphorylation at Ser36 downstream of integrin α5β1 and c-Jun N-terminal kinase. In parallel, nicotinamide adenine dinucleotide phosphate oxidase activation, as well as production of reactive oxygen species, increased, whereas nitric oxide bioavailability decreased. Silencing of p66Shc blunted stretch-increased superoxide anion production and nicotinamide adenine dinucleotide phosphate oxidase activation and restored nitric oxide bioavailability. In line with the above, activation of p66Shc increased in isolated aortic endothelial cells of spontaneously hypertensive rats compared with normotensive ones. Pathological stretch by activating ...
Source: Hypertension - Category: Cardiology Authors: Tags: Endothelium/vascular type/nitric oxide Source Type: research