Endothelial S100A1 Modulates Vascular Function via Nitric Oxide

S. T. Pleger, D. M. Harris, C. Shan, L. E. Vinge, J. K. Chuprun, B. Berzins, W. Pleger, C. Druckman, M. Volkers, J. Heierhorst, E. Oie, A. Remppis (+5 others)
2008 Circulation Research  
S100A1, a Ca 2ϩ -binding protein of the EF-hand type, is known to modulate sarcoplasmic reticulum Ca 2ϩ handling in skeletal muscle and cardiomyocytes. Recently, S100A1 has been shown to be expressed in endothelial cells (ECs). Because intracellular Ca 2ϩ ([Ca 2ϩ ] 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
more » ... cic 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 [Ca 2ϩ ] i transients in ECs. Consistently, silencing endothelial S100A1 expression in wild type also reduced [Ca 2ϩ ] 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 [Ca 2ϩ ] 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. (Circ Res. 2008;102:786-794.) Key Words: S100A1 Ⅲ vascular function Ⅲ NO Ⅲ hypertension Ⅲ endothelial function Ⅲ calcium S 100A1 is a low-molecular-weight (Ϸ10-kDa) Ca 2ϩsensing protein of the EF-hand type known to modulate intracellular Ca 2ϩ ([Ca 2ϩ ] i ) handling in skeletal muscle and cardiomyocytes. 1-3 S100A1 has been shown to affect cardiac contractile performance through enhanced sarcoplasmic reticulum Ca 2ϩ cycling, modulation of myofilament function, and regulation of mitochondrial function. 4 -10 S100A1 is especially interesting with respect to cardiovascular diseases because cardiac S100A1 expression levels are significantly downregulated in end-stage heart failure (HF) and the normalization of S100A1 protein expression has been shown to rescue the failing myocardium in vivo. 3, [11] [12] [13] [14] Recently S100A1 expression has been described in endothelial cells (ECs). 15 A well-characterized and critical regulator of endothelial function is NO, which is generated by endothelial NO synthase (eNOS or NOS3). 16 Activation of eNOS is classically dependent on increased [Ca 2ϩ ] i , which can be induced by agonists such as acetylcholine (ACh) or bradykinin (BK). 17,18 NO contributes to endothelium-dependent vascular relaxation and has additional functional roles, such as leukocyte adhesion and antiproliferative and antiapoptotic effects on the vascular wall. 17,19 Importantly, endothelial dysfunction occurs in a variety of cardiovascular diseases and was found to be associated with adverse effects such as inflammation, impaired vascular function, and long-term vascular remodeling. 20 Moreover, recent data provide evidence that endothelial dysfunction in HF is associated with an increased mortality risk in patients with both ischemic and nonischemic HF. 21 Original
doi:10.1161/circresaha.108.172031 pmid:18292599 fatcat:isrkarrfnrawtgkf4wlkznjlee