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(Circulation Research. 2008;102:786.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Endothelial S100A1 Modulates Vascular Function via Nitric Oxide

Sven T. Pleger, David M. Harris, Changguang Shan, Leif E. Vinge, J. Kurt Chuprun, Brett Berzins, Wiebke Pleger, Charles Druckman, Mirko Völkers, Jörg Heierhorst, Erik Øie, Andrew Remppis, Hugo A. Katus, Rosario Scalia, Andrea D. Eckhart, Walter J. Koch^*, Patrick Most^*

From the Center for Translational Medicine, George Zallie and Family Laboratory for Cardiovascular Gene Therapy (S.T.P., L.E.V., J.K.C., W.P., W.J.K.), Laboratory for Cardiac Stem Cell & Gene Therapy (P.M.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (D.M.H., C.D., A.D.E.), Department of Physiology (B.B., R.S.), Thomas Jefferson University, Philadelphia, Pa; Laboratory for Cardiac Stem Cell & Gene Therapy, (S.T.P., C.S., M.V., A.R., H.A.K., P.M.), Medizinische Universitätsklinik und Poliklinik III, Otto Meyerhof Zentrum, Universität Heidelberg, Germany; Department of Cardiology (E.Ø.) and Institute for Surgical Research (L.E.V.), Rikshospitalet Medical Center and University of Oslo, Norway; and St-Vincent’s Institute of Medical Research and Department of Medicine (J.H.), Fitzroy, Victoria, Australia.

Correspondence to Patrick Most, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pa 19107. E-mail patrick.most{at}jefferson.edu

S100A1, a Ca²⁺-binding protein of the EF-hand type, is known to modulate sarcoplasmic reticulum Ca²⁺ handling in skeletal muscle and cardiomyocytes. Recently, S100A1 has been shown to be expressed in endothelial cells (ECs). Because intracellular Ca²⁺ ([Ca²⁺]_i) transients can be involved in important EC functions and endothelial NO synthase activity, we sought to investigate the impact of endothelial S100A1 on the regulation of endothelial and vascular function. Thoracic aortas from S100A1 knockout mice (SKO) showed significantly reduced relaxation in response to acetylcholine compared with wild-type vessels, whereas direct vessel relaxation using sodium nitroprusside was unaltered. Endothelial dysfunction attributable to the lack of S100A1 expression could also be demonstrated in vivo and translated into hypertension of SKO. Mechanistically, both basal and acetylcholine-induced endothelial NO release of SKO aortas was significantly reduced compared with wild type. Impaired endothelial NO production in SKO could be attributed, at least in part, to diminished agonist-induced [Ca²⁺]_i transients in ECs. Consistently, silencing endothelial S100A1 expression in wild type also reduced [Ca²⁺]_i and NO generation. Moreover, S100A1 overexpression in ECs further increased NO generation that was blocked by the inositol-1,4,5-triphosphate receptor blocker 2-aminoethoxydiphenylborate. Finally, cardiac endothelial S100A1 expression was shown to be downregulated in heart failure in vivo. Collectively, endothelial S100A1 critically modulates vascular function because lack of S100A1 expression leads to decreased [Ca²⁺]_i and endothelial NO release, which contributes, at least partially, to impaired endothelium-dependent vascular relaxation and hypertension in SKO mice. Targeting endothelial S100A1 expression may, therefore, be a novel therapeutic means to improve endothelial function in vascular disease or heart failure.

Key Words: S100A1 • vascular function • NO • hypertension • endothelial function • calcium

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