Leptin Locally Synthesized in Carotid Atherosclerotic Plaques Could Be Associated With Lesion Instability and Cerebral Emboli

Abstract

Background

Unstable carotid plaques cause cerebral emboli. Leptin promotes atherosclerosis and vessel wall remodeling. We hypothesized that carotid atherosclerotic lesion instability is associated with local leptin synthesis.

Methods and Results

Carotid endarterectomy plaques from symptomatic (n=40) and asymptomatic patients with progressive stenosis (n=38) were analyzed for local expression of leptin, tumor necrosis factor (TNF)-α, and plasminogen activator inhibitor type 1. All lesions exhibited advanced atherosclerosis inclusive of thick- and thin-cap fibroatheromas or lesion rupture. Symptomatic lesions exhibited more plaque ruptures and macrophage infiltration ( P=0.001 and P=0.05, respectively). Symptomatic plaques showed preferential leptin, TNF-α, and plasminogen activator inhibitor type 1 transcript ( P=0.03, P=0.04, and P=0.05, respectively). Leptin mRNA and antigen in macrophages and smooth muscle cells were confirmed by in situ hybridization and immunohistochemistry. Plasma leptin levels were not significantly different between groups ( P=1.0), whereas TNF-α was significantly increased in symptomatic patients ( P=0.006). Human aortic smooth muscle cell culture stimulated by TNF-α, lipopolysaccharide, or lipoteichoic acid revealed 6-, 6.7-, and 6-fold increased secreted leptin antigen, respectively, at 72 hours ( P<0.05).

Conclusions

Neurologically symptomatic patients overexpress leptin mRNA and synthesize leptin protein in carotid plaque macrophages and smooth muscle cells. Local leptin induction, presumably by TNF-α, could exert paracrine or autocrine effects, thereby contributing to the pathogenesis of lesion instability.

Clinical Trial Registration

URL: www.Clinicaltrials.gov. Unique identifier: NCT00449306.

Journal

Journal ID (nlm-ta): J Am Heart Assoc

Journal ID (iso-abbrev): J Am Heart Assoc

Journal ID (hwp): ahaoa

Journal ID (publisher-id): jah3

Title: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Publisher: Blackwell Publishing Ltd

ISSN (Electronic): 2047-9980

Publication date Collection: October 2012

Publication date (Electronic): 25 October 2012

Volume: 1

Issue: 5

Affiliations

[1 ]Department of Vascular Surgery and the Gottesdiener Vascular Biology Laboratory, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel (J.S., M.H., I.E.)

[2 ]Institute of Thrombosis and Hemostasis, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel (R.D.)

[3 ]Sheba Cancer Research Center and Institute of Hematology, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel (A.J.S.)

[4 ]Institute of Endocrinology, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel (C.P.)

[5 ]Department of Cardiology and Pulmonary Medicine, University Medicine Goettingen, Germany (N.S., S.K.-E.)

[6 ]CVPath Institute, Inc, Gaithersburg, MD (K.S.)

[7 ]Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Israel (F.D.K., R.V.)

[8 ]Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece (S.K.)

Author notes

Correspondence to: Jacob Schneiderman, MD, Sackler Faculty of Medicine, Tel Aviv University, The Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail jschneid72@ 123456yahoo.com

Article

Publisher ID: jah375

DOI: 10.1161/JAHA.112.001727

PMC ID: 3541612

PubMed ID: 23316287

Copyright statement: © 2012 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell.

License:

This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Categories

Subject: Original Research

Subject: Stroke