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

Abstract

BackgroundUnstable 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 ResultsCarotid 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).ConclusionsNeurologically 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 RegistrationURL: www.Clinicaltrials.gov. Unique identifier: NCT00449306.

Locally Applied Leptin Induces Regional Aortic Wall Degeneration Preceding Aneurysm Formation in Apolipoprotein E–Deficient Mice

“…Although in vivo mechanisms capable of inducing leptin in the vessel wall were beyond the scope of this study, we should consider a possible scenario in which leptin is locally induced by both systemic and local cytokines like TNFα, as elicited by active inflammation or recurrent bacterial infections. 28 Interestingly, TNFα is abundantly expressed in AAA wall, and an experimental mouse model has demonstrated its critical role in AAA genesis. 58,59 …”

“…Levels of leptin mRNA in the plaque correlated with lesion instability, suggesting a role for leptin in plaque remodeling. 28 In pursuit of vascular systems that might similarly undergo long term remodeling processes, we postulated that leptin may play a role in early mechanisms of AAA pathogenesis, through modulation of the ECM. We have confirmed de novo synthesis of leptin within human aortic aneurysm wall.…”

Differences between perivascular adipose tissue surrounding the heart and the internal mammary artery: possible role for the leptin-inflammation-fibrosis-hypoxia axis

“…In situ hybridization analysis of leptin mRNA expression was performed on 5-lm-thick paraffin sections, as described [27].…”

Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling

“…Leptin is mostly synthesized by adipocytes, and its systemic levels correlate with body fat mass 17. Leptin synthesis is induced to a lesser extent in macrophages and vascular smooth muscle cells (SMCs) by cytokines and AngII, resulting in local cardiovascular pathological conditions 18. Hyperleptinemia is a risk factor for symptomatic cardiovascular disease, mainly through increased arterial blood pressure, augmented oxidative stress, stiffening of the vascular wall, and vascular cell calcification 19, 20, 21, 22, 23…”

“…17 Leptin synthesis is induced to a lesser extent in macrophages and vascular smooth muscle cells (SMCs) by cytokines and AngII, resulting in local cardiovascular pathological conditions. 18 Hyperleptinemia is a risk factor for symptomatic cardiovascular disease, mainly through increased arterial blood pressure, augmented oxidative stress, stiffening of the vascular wall, and vascular cell calcification. [19][20][21][22][23] In the clinical setting, aging-related arterial stiffening 24 promotes left ventricular hypertrophy (LVH) via complex interactions among elevated systemic blood pressure, increased pulse pressure, diminished arterial distensiblity, and augmented left ventricular (LV) afterload.…”