Background: Ischaemic cardiovascular disease, including myocardial infarction and stroke, is the leading cause of morbidity and mortality worldwide. Atherosclerosis and coronary artery disease, which underpin ischaemic cardiovascular disorders, are characterised by chronic inflammation of the blood vessel wall and endothelial dysfunction. C-type natriuretic peptide (CNP) has recently been identified as an endothelium-derived hyperpolarising factor with anti-atherogenic properties. The studies described herein investigated the hypothesis that the vasoprotective profile of CNP includes opposing effects on endothelial and vascular smooth muscle cell proliferation and regulation of blood pressure. Methods: Cellular incorporation of bromodeoxyuridine was used to determine cell proliferation and immunoblotting was employed to assess expression/activity of intracellular signalling proteins in human umbilical vein endothelial cells (HUVEC) and rat aortic smooth muscle cells (RAoSMC). An endothelium specific CNP knockout (ecCNP KO) mouse model was developed and organ bath pharmacology utilised to assess vascular reactivity in vitro, and radiotelemetric monitoring used to determine blood pressure in vivo. Principal findings: CNP augmented HUVEC proliferation in a natriuretic peptide receptor (NPR)-Cdependent fashion by up-regulating the cell cycle promoter, cyclin D1. In contrast, CNP increased expression of the cell cycle inhibitors p21waf1/cip1/p27kip1 in RAoSMC and reduced cell growth; the pro- and anti-mitogenic effects of CNP were mediated in an extracellular signal-regulated kinase (ERK) 1/2-dependent manner. Vascular reactivity and endothelial function were disrupted in isolated aortae from female ecCNP KO mice compared to WT, whilst in males was unchanged. Female ecCNP KO mice were hypertensive. Conclusions: The anti-atherogenic properties of CNP are mediated in part by NPR-C and ERK 1/2 signalling, resulting in a differential regulation of cell cycle proteins that promotes endothelial cell proliferation and inhibits smooth muscle cell growth. Moreover, endothelium-derived CNP is key to blood pressure regulation in females. These data suggest that targeting CNP/NPR-C signalling may represent a novel approach for the treatment of cardiovascular disease.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:565044 |
| Date | January 2010 |
| Creators | Khambata, R. S. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/133897/ |
Page generated in 0.0026 seconds