Article

Inhibition of pathological differentiation of valvular 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: 6.34). 05/2011; 31(8):1881-9. DOI: 10.1161/ATVBAHA.111.223974
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
141 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Calcific aortic valve disease (CAVD) affects 25% of people over 65, and the late-stage stenotic state can only be treated with total valve replacement, requiring 85,000 surgeries annually in the US alone [1]. As CAVD is an age-related disease, many of the affected patients are unable to undergo the open-chest surgery that is its only current cure. This challenge motivates the elucidation of the mechanisms involved in calcification, with the eventual goal of alternative preventative and therapeutic strategies. There is no sufficient animal model of CAVD, so we turn to potential in vitro models. In general, in vitro models have the advantages of shortened experiment time and better control over multiple variables compared to in vivo models. As with all models, the hypothesis being tested dictates the most important characteristics of the in vivo physiology to recapitulate. Here, we collate the relevant pieces of designing and evaluating aortic valve calcification so that investigators can more effectively draw significant conclusions from their results.
    Cardiovascular Pathology 08/2014; · 2.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Valvular interstitial cells (VICs), the fibroblast-like cellular constituents of aortic heart valves, maintain structural integrity of valve tissue. Activation into contractile myofibroblasts occurs under pathological situations and under standard cell culture conditions of isolated VICs. Reversal of this phenotype switch would be of major importance in respect to fibrotic valve diseases. In this investigation, we found that exogenous polyunsaturated fatty acids (PUFAs) decreased contractility and expression of myofibroblastic markers like α-smooth muscle actin (αSMA) in cultured VICs from porcine aortic valves. The most active PUFAs, docosahexaenoic acid (DHA) and arachidonic acid (AA) reduced the level of active RhoA and increased the G/F-actin ratio. The G-actin-regulated nuclear translocation of myocardin-related transcription factors (MRTFs), co-activators of serum response factor, was also reduced by DHA and AA. The same effects were observed after blocking RhoA directly with C3 transferase. In addition, increased contractility after induction of actin polymerisation with jasplakinolide and concomitant expression of αSMA were ameliorated by active PUFAs. Furthermore, reduced αSMA expression under PUFA exposure was observed in valve tissue explants demonstrating physiological relevance. In conclusion, RhoA/G-actin/MRTF signalling is operative in VICs, and this pathway can be partially blocked by certain PUFAs whereby the activation into the myofibroblastic phenotype is reversed.
    Journal of Molecular and Cellular Cardiology 05/2014; · 5.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    Global cardiology science & practice. 01/2014; 2014(1):52-77.

Full-text (3 Sources)

Download
7 Downloads
Available from
Oct 17, 2014