Abstract 15302: Accelerated Atherogenesis and Diminished Vascular Integrity in Mice Lacking Endothelial C-Type Natriuretic Peptide
Background: C-type natriuretic peptide (CNP) is an endothelium-derived vasorelaxant important in the regulation of local blood flow and systemic blood pressure. Exogenous CNP has been shown to exert anti-inflammatory, anti-atherogenic effects in vitro, including inhibition of leukocyte recruitment, platelet activation, and smooth muscle cell proliferation. Herein, we have generated a novel endothelial cell-specific CNP knockout (ecCNP KO) mouse to investigate a potential cardioprotective role of endogenous CNP in vivo.
Methods: CNP was selectively deleted from the endothelium by crossing a CNPflox/flox animal with a Tie2-Cre transgenic mouse. Wildtype (WT) littermate controls were used for all experiments. Basal and IL-1β (5ng)-stimulated leukocyte recruitment was assessed by intravital microscopy. Basal and PAR4-AP (300µM)-stimulated platelet P-selectin expression (marker of platelet activation) in whole blood was measured by flow cytometry. ApoE KO mice were crossed with ecCNP KO animals and fed a high fat diet for 12 weeks to investigate the effect of endothelial CNP deletion on atherogenesis.
Results: Leukocyte rolling was significantly higher in ecCNP KO mice compared to WT animals under basal conditions (WT=9.2±1.3 cells/min versus KO=21.1±0.9 cells/min; P=0.002; n=12) and following administration of IL-1β (WT=28.6±1.1 cells/min versus KO=46.6±0.3 cells/min; P<0.0001; n=12). Basal (WT=0.27±0.08% versus KO=0.57±0.07%, P=0.02; n=9) and PAR4-AP-stimulated (WT=25.9±3.6% versus KO=41.0±5.3%; P=0.01; n=9) platelet P-selectin expression was higher in ecCNP KO mice compared to WT. ApoE/ecCNP double KO animals fed a high fat diet exhibited greater atherosclerotic plaque formation in the aorta than ecCNP WT/ApoE KO mice (WT=6.8±0.5% versusKO=11.4±1.2%; P=0.0008; n=18). Moreover, 40% of the ecCNP/ApoE double KO mice developed aneurysms in the aortic arch and/or abdominal aorta.
Conclusion: These findings demonstrate that a loss of endothelial CNP is detrimental to vascular integrity, establishing the importance of this peptide in regulating inflammation, platelet activation and atherogenesis in vivo. Thus, CNP represents a promising target for therapeutic intervention in inflammatory cardiovascular disorders.
- © 2012 by American Heart Association, Inc.