Inhibition of Pathological Differentiation of Valve Interstitial Cells by C-Type Natriuretic Peptide

Institute of Biomaterials and Biomedical Engineering, University of Toronto, Ontario, Canada.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 05/2011; 31(8):1881-9. DOI: 10.1161/ATVBAHA.111.223974
Source: PubMed


Calcific aortic valve disease is associated with the differentiation of valvular interstitial cells (VICs) to myofibroblast and osteoblast-like cells, particularly in the fibrosa layer of the valve. Previous studies suggested that C-type natriuretic peptide (CNP) protects against calcific aortic valve disease to maintain homeostasis. We aimed to determine whether CNP inhibits VIC pathological differentiation as a mechanism to explain its protective effects.
CNP expression was prominent in normal porcine aortic valves, particularly on the ventricular side, but reduced in sclerotic valves concomitant with the appearance of pathological VIC phenotypes in the fibrosa. In vitro, CNP inhibited calcified aggregate formation and bone-related transcript and protein expression by VICs grown in osteogenic conditions. Under myofibrogenic culture conditions, CNP reduced α-smooth muscle actin expression and cell-mediated gel contraction, indicating inhibition of myofibroblast differentiation. Similar to CNP, simvastatin inhibited VIC osteoblast and myofibroblast differentiation in vitro. Strikingly, simvastatin upregulated CNP expression in VICs cultured under myofibrogenic conditions, and small interfering RNA knockdown of natriuretic peptide receptor-b (a CNP receptor) significantly reduced the antifibrotic effect of simvastatin, suggesting that it acts in part via CNP/NPR-B autocrine/paracrine signaling.
CNP inhibits myofibroblast and osteoblast differentiation of VICs and is responsible in part for inhibition of VIC myofibroblast differentiation by statins, suggesting novel mechanisms to explain the protective effect of CNP and the pleiotropic effects of statins in the aortic valve.

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Available from: Mark C Blaser, Oct 17, 2014
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    • "ves its effects by causing an increase in the levels of cyclic guanosine monophosphate (cGMP). Another mediator expressed by valve endothelial cells, which also activates cGMP, is C-type natriuretic peptide (CNP). 162 This peptide also has anti-calcification effects on valve interstitial cells due to its activity at natriuretic peptide receptor-b. 163 In addition, it has been established that expression of CNP is reduced in the valves of patients with aortic stenosis. 162 The paracrine effects of NO and CNP suggest a role for a cGMP-dependent mechanism in the interstitial cells that suppresses the differentiation of cells within the valve towards an osteoblast/calcifying phenotype. "
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    • "For example, we identified greater expression of OPG, CNP, and chordin on the disease-protected ventricular side of normal leaflets [5]. Each of these secreted proteins is putatively protective: OPG suppresses cardiovascular calcification [44], and in its absence, receptor activator of NF-κB ligand (RANKL) is able to bind RANK on VICs to cause elevated MMP-1 and MMP-2 activities [45], DNA binding activity of Runx2, bone-related matrix protein expression, and calcification in vitro [46]; CNP inhibits myofibroblast and osteogenic differentiation of VICs in vitro [47]; and chordin is a BMP antagonist. "
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