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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:195.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Soluble N-Cadherin Overexpression Reduces Features of Atherosclerotic Plaque Instability

Cressida A. Lyon; Jason L. Johnson; Helen Williams; Graciela B. Sala-Newby; Sarah J. George

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

Correspondence to Dr Sarah Jane George, Bristol Heart Institute, Level 7, Bristol Royal Infirmary, BRISTOL, BS2 8HW, United Kingdom. E-mail s.j.george{at}bris.ac.uk

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.

Key Words: apoptosis • atherosclerosis • cell adhesion molecules • smooth muscle • macrophages