Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 116, Issue -, Pages 5-15Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2018.01.010
Keywords
p27; p27 phosphorylation at serine 10; Cox-2; Endothelial cell; Aneurysm; Vascular contractility
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Funding
- Spanish Ministerio de Economia, Industria y Competitividad (MEIC) [SAF2013-46663-R, SAF2016-79490-R]
- Instituto de Salud Carlos III [RD12/0042/0028, RD12/0042/22, PI1100406]
- Fondo Europeo de Desarrollo Regional (FEDER)
- Spanish Ministerio de Educacion [AP2009-01833]
- MEIC [FPDI-2013-17423, SEV-2015-0505]
- Red de Investigacion Cardiovascular (RETIC Program, Instituto de Salud Carlos III)
- MEIC
- Pro-CNIC Foundation
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Phosphorylation at serine 10 (S10) is the major posttranslational modification of the tumor suppressor p27, and is reduced in both human and mouse atherosclerosis. Moreover, a lack of p27-phospho-S10 in apolipoprotein E-null mice (apoE-/-) leads to increased high-fat diet-induced atherosclerosis associated with endothelial dysfunction and augmented leukocyte recruitment. In this study, we analyzed whether p27-phospho-S10 modulates additional endothelial functions and associated pathologies. Defective p27-phospho-S10 increases COX-2 activity in mouse aortic endothelial cells without affecting other key regulators of vascular reactivity, reduces endothelium-dependent dilation, and increases arterial contractility. Lack of p27-phospho-S10 also elevates aortic COX-2 expression and thromboxane A2 production, increases aortic lumen diameter, and aggravates angiotensin II-induced abdominal aortic aneurysm development in apoE-/- mice. All these abnormal responses linked to defective p27-phospho-S10 are blunted by pharmacological inhibition of COX-2. These results demonstrate that defective p27-phospho-S10 modifies endothelial behavior and promotes aneurysm formation via COX-2 activation.
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