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MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis
Bishuang Cai, … , Gabrielle Fredman, Ira Tabas
Bishuang Cai, … , Gabrielle Fredman, Ira Tabas
Published January 9, 2017
Citation Information: J Clin Invest. 2017;127(2):564-568. https://doi.org/10.1172/JCI90520.
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Brief Report Vascular biology

MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis

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Abstract

Atherothrombotic vascular disease is often triggered by a distinct type of atherosclerotic lesion that displays features of impaired inflammation resolution, notably a necrotic core and thinning of a protective fibrous cap that overlies the core. A key cause of plaque necrosis is defective clearance of apoptotic cells, or efferocytosis, by lesional macrophages, but the mechanisms underlying defective efferocytosis and its possible links to impaired resolution in atherosclerosis are incompletely understood. Here, we provide evidence that proteolytic cleavage of the macrophage efferocytosis receptor c-Mer tyrosine kinase (MerTK) reduces efferocytosis and promotes plaque necrosis and defective resolution. In human carotid plaques, MerTK cleavage correlated with plaque necrosis and the presence of ischemic symptoms. Moreover, in fat-fed LDL receptor–deficient (Ldlr–/–) mice whose myeloid cells expressed a cleavage-resistant variant of MerTK, atherosclerotic lesions exhibited higher macrophage MerTK, lower levels of the cleavage product soluble Mer, improved efferocytosis, smaller necrotic cores, thicker fibrous caps, and increased ratio of proresolving versus proinflammatory lipid mediators. These findings provide a plausible molecular-cellular mechanism that contributes to defective efferocytosis, plaque necrosis, and impaired resolution during the progression of atherosclerosis.

Authors

Bishuang Cai, Edward B. Thorp, Amanda C. Doran, Brian E. Sansbury, Mat J.A.P. Daemen, Bernhard Dorweiler, Matthew Spite, Gabrielle Fredman, Ira Tabas

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Figure 1

Sol-Mer is increased in advanced human and murine atherosclerotic lesions.

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Sol-Mer is increased in advanced human and murine atherosclerotic lesion...
(A) Carotid endarterectomy (CEA) specimens were analyzed for sol-Mer by immunoblot, and necrotic area was measured from H&E-stained images. The correlation coefficient (R) and P value were based on Pearson’s product-moment correlation analysis. (B) CEA specimens from asymptomatic and symptomatic patients were assessed by immunoblot for sol-Mer (n = 5 per group). β-Actin and MAC2 were used as loading controls for total protein and macrophages, respectively. (C) Paraffin-embedded CEA sections were stained with anti-MerTK antibody, imaged by confocal microscopy (scale bar: 30 μm), and quantified by MerTK mean fluorescence intensity (MFI) relative to the asymptomatic cohort (n = 6–8 for each group). *P < 0.05, by 2-tailed Student’s t test. (D) Age-matched Ldlr–/– mice were fed the Western-type diet (WD) for 0, 8, or 16 weeks and sacrificed at 24 weeks of age. The aortic arch, Brachiocephalic Artery (BCA), and descending aorta up to the renal bifurcation were removed en bloc and immunoblotted for sol-Mer (n = 3 per group).

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