Adaptor protein p66(Shc) mediates hypertension-associated, cyclic stretch-dependent, endothelial damage.
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 p66(Shc) protects mice against age-related and hyperglycemia-induced endothelial dysfunction, as well as atherosclerosis and stroke. Furthermore, p66(Shc) mediates vascular dysfunction in hypertensive mice. However, the direct role of p66(Shc) in mediating mechanical force-induced free radical production is unknown; thus, we studied the effect of cyclic stretch on p66(Shc) 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 p66(Shc) 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 p66(Shc) 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 p66(Shc) increased in isolated aortic endothelial cells of spontaneously hypertensive rats compared with normotensive ones. Pathological stretch by activating integrin α5β1 and c-Jun N-terminal kinase phosphorylates p66(Shc) at Ser36, augments reactive oxygen species production via nicotinamide adenine dinucleotide phosphate oxidase, and in turn reduces nitric oxide bioavailability. This novel molecular pathway may be relevant for endothelial dysfunction and vascular disease in hypertension.
From the Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland (R.D.S., M.G., B.S., F.W., S.K., A.A., F.C.T., T.F.L., G.G.C.); Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (R.D.S., M.G., B.S., S.K., A.A., F.C.T., T.F.L., G.G.C.); and Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland (F.C.T., T.F.L.).
Remo D
RD
Spescha
From the Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland (R.D.S., M.G., B.S., F.W., S.K., A.A., F.C.T., T.F.L., G.G.C.); Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (R.D.S., M.G., B.S., S.K., A.A., F.C.T., T.F.L., G.G.C.); and Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland (F.C.T., T.F.L.).
Martina
M
Glanzmann
From the Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland (R.D.S., M.G., B.S., F.W., S.K., A.A., F.C.T., T.F.L., G.G.C.); Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (R.D.S., M.G., B.S., S.K., A.A., F.C.T., T.F.L., G.G.C.); and Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland (F.C.T., T.F.L.).
Branko
B
Simic
From the Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland (R.D.S., M.G., B.S., F.W., S.K., A.A., F.C.T., T.F.L., G.G.C.); Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (R.D.S., M.G., B.S., S.K., A.A., F.C.T., T.F.L., G.G.C.); and Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland (F.C.T., T.F.L.).
Fabienne
F
Witassek
From the Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland (R.D.S., M.G., B.S., F.W., S.K., A.A., F.C.T., T.F.L., G.G.C.); Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (R.D.S., M.G., B.S., S.K., A.A., F.C.T., T.F.L., G.G.C.); and Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland (F.C.T., T.F.L.).
Stephan
S
Keller
From the Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland (R.D.S., M.G., B.S., F.W., S.K., A.A., F.C.T., T.F.L., G.G.C.); Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (R.D.S., M.G., B.S., S.K., A.A., F.C.T., T.F.L., G.G.C.); and Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland (F.C.T., T.F.L.).
Alexander
A
Akhmedov
From the Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland (R.D.S., M.G., B.S., F.W., S.K., A.A., F.C.T., T.F.L., G.G.C.); Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (R.D.S., M.G., B.S., S.K., A.A., F.C.T., T.F.L., G.G.C.); and Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland (F.C.T., T.F.L.).
Felix C
FC
Tanner
From the Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland (R.D.S., M.G., B.S., F.W., S.K., A.A., F.C.T., T.F.L., G.G.C.); Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (R.D.S., M.G., B.S., S.K., A.A., F.C.T., T.F.L., G.G.C.); and Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland (F.C.T., T.F.L.).
Thomas F
TF
Lüscher
From the Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland (R.D.S., M.G., B.S., F.W., S.K., A.A., F.C.T., T.F.L., G.G.C.); Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (R.D.S., M.G., B.S., S.K., A.A., F.C.T., T.F.L., G.G.C.); and Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland (F.C.T., T.F.L.). giovannic@access.uzh.ch.
Giovanni G
GG
Camici
D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000503:physiopathology; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D051381:Rats; D011918:Rats, Inbred SHR; D017382:Reactive Oxygen Species / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*
D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; D048031:JNK Mitogen-Activated Protein Kinases
endothelium; hypertension; nitric oxide; reactive oxygen species; stress, mechanical