5 research outputs found
Investigation of the vasoprotective role of C-type natriuretic peptide
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