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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    ABSTRACT: The aortic valve lies in a unique hemodynamic environment, one characterized by a range of stresses (shear stress, bending forces, loading forces and strain) that vary in intensity and direction throughout the cardiac cycle. Yet, despite its changing environment, the aortic valve opens and closes over 100,000 times a day and, in the majority of human beings, will function normally over a lifespan of 70-90 years. Until relatively recently heart valves were considered passive structures that play no active role in the functioning of a valve, or in the maintenance of its integrity and durability. However, through clinical experience and basic research the aortic valve can now be characterized as a living, dynamic organ with the capacity to adapt to its complex mechanical and biomechanical environment through active and passive communication between its constituent parts. The clinical relevance of a living valve substitute in patients requiring aortic valve replacement has been confirmed. This highlights the importance of using tissue engineering to develop heart valve substitutes containing living cells which have the ability to assume the complex functioning of the native valve.
    Full-text · Article · Jan 2014
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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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    ABSTRACT: In calcific aortic valve disease, fibrotic and calcific lesions form focally in the fibrosa layer of the valve leaflets. Layer-specific pathosusceptibility suggests that the fibrosa microenvironment is permissive to pathological development. The cellular microenvironment in the aortic valve is defined by a variety of biomechanical-, biochemical-, and extracellular-mediated factors, some of which are unique to the fibrosa. Growing evidence supports the role of these microenvironmental cues in the local regulation of side-specific valve cell phenotypes and focal pathological alterations, revealing new insights into the cellular and molecular processes that contribute to calcific aortic valve disease.
    Preview · Article · May 2011 · Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology
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    ABSTRACT: The hallmarks of calcific aortic valve disease (CAVD) are the significant changes that occur in the organization, composition, and mechanical properties of the extracellular matrix (ECM), ultimately resulting in stiffened stenotic leaflets that obstruct flow and compromise cardiac function. Increasing evidence suggests that ECM maladaptations are not simply a result of valve cell dysfunction; they also contribute to CAVD progression by altering cellular and molecular signaling. In this review, we summarize the ECM changes that occur in CAVD. We also discuss examples of how the ECM influences cellular processes by signaling through adhesion receptors (matricellular signaling), by regulating the presentation and availability of growth factors and cytokines to cells (matricrine signaling), and by transducing externally applied forces and resisting cell-generated tractional forces (mechanical signaling) to regulate a wide range of pathological processes, including differentiation, fibrosis, calcification, and angiogenesis. Finally, we suggest areas for future research that should lead to new insights into bidirectional cell-ECM interactions in the aortic valve, their contributions to homeostasis and pathobiology, and possible targets to slow or prevent the progression of CAVD.
    Preview · Article · Jun 2011 · Circulation Research
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