Soluble N-Cadherin Overexpression Reduces Features of Atherosclerotic Plaque Instability

Author:

Lyon Cressida A.1,Johnson Jason L.1,Williams Helen1,Sala-Newby Graciela B.1,George Sarah J.1

Affiliation:

1. From the Bristol Heart Institute, Bristol Royal Infirmary, UK.

Abstract

Objectives— Vascular smooth muscle cell (VSMC) apoptosis contributes to atherosclerotic plaque instability and myocardial infarction. Consequently, reducing VSMC apoptosis may be beneficial for reducing plaque instability and acute coronary events. We previously demonstrated that N-cadherin, a cell-cell adhesion molecule, reduces VSMC apoptosis in vitro. In this study, we examined whether a soluble form of N-cadherin (SNC) affected VSMC apoptosis and plaque stability. Methods and Results— SNC significantly inhibited VSMC apoptosis in vitro by ≈50% via activation of fibroblast growth factor receptor, phosphoinositide-3 kinase, and Akt signaling. SNC also significantly reduced macrophage and foam cell-macrophage apoptosis in vitro by >50%, without affecting monocyte invasion or macrophage proliferation. Elevation of plasma levels of SNC in male apolipoprotein E-deficient mice with existing atherosclerosis via adenoviral delivery significantly reduced VSMC and macrophage apoptosis in brachiocephalic artery plaques by ≈60%. Additionally, SNC promoted plaques of a more stable phenotype by elevating VSMC:macrophage ratio and presence of VSMC-rich fibrous cap, as well as attenuating macrophage number and incidence of buried fibrous caps (a surrogate plaque rupture marker). Conclusions— In summary, this study demonstrates that SNC suppressed plaque instability by attenuation of apoptosis, suggesting that SNC may have a therapeutic potential for retarding plaque instability.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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