The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer

Abdominal obesity is a major risk factor for cardiovascular disease, and recent studies highlight a key role of adipose tissue dysfunction, inflammation, and aberrant adipokine release in this process. An increased demand for lipid storage results in both hyperplasia and hypertrophy, finally leading to chronic inflammation, hypoxia, and a phenotypic change of the cellular components of adipose tissue, collectively leading to a substantially altered secretory output of adipose tissue. In this review we have assessed the adipo-vascular axis, and an overview of adipokines associated with cardiovascular disease is provided. This resulted in a first list of more than 30 adipokines. A deeper analysis only considered adipokines that have been reported to impact on inflammation and NF-κB activation in the vasculature. Out of these, the most prominent link to cardiovascular disease was found for leptin, TNF-α, adipocyte fatty acid-binding protein, interleukins, and several novel adipokines such as lipocalin-2 and pigment epithelium-derived factor. Future work will need to address the potential role of these molecules as biomarkers and/or drug targets.

https://www.physiology.org/doi/pdf/10.1152/ajpheart.00907.2011

Inflammation and metabolic dysfunction: links to cardiovascular diseases

Background
Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury (AKI) Recently, elevated NGAL levels have also been reported in heart failure, coronary heart disease, and stroke Other studies demonstrate that NGAL is upregulated in failing myocardium and in atherosclerotic plaque Our aim was to synthesize the current evidence on NGAL and cardiovascular disease (CVD), and to clarify the prognostic significance of systemic NGAL levels in CVD

/pdf/neutrophil-gelatinase-associated-lipocalin-as-a-biomarker-of-5gqeb2z366.pdf

Neutrophil gelatinase-associated lipocalin as a biomarker of cardiovascular disease: a systematic review

Neutrophil Gelatinase-Associated Lipocalin (NGAL) is Associated with Symptomatic Carotid Atherosclerosis and Drives Pro-inflammatory State In Vitro

The aim of this review is to overview the pathophysiological role of adipocytokines in atherogenesis, focusing on their potential role as biomarkers of coronary disease. Several lines of evidence indicated adipose tissue not only as depot but rather as an endocrine organ. In this context, the balance between pro- and anti-inflammatory adipocytokines has been shown to critically regulate vascular homeostasis in both physiological and pathophysiological conditions. Overweight and obesity are characterized by dysfunctional adipose tissue and then the prevalence of pro-inflammatory mediators, with a detrimental effect on vascular health. As opposite to adiponectin, pro-inflammatory adipocytokines, such as leptin and resistin, promote endothelial dysfunction and inflammatory processes involved in atherosclerotic plaque progression and vulnerability. Therefore, many adipocytokines have been investigated as potential biomarkers of cardiovascular (CV) risk, but their role has not yet been clearly established. Furthermore, the perivascular adipose tissue recently emerged as a critical modulator of atherosclerotic processes, due to the close interaction with the underlying vascular tissue. The ongoing discovery of new adipocytokines and the complex pathophysiological role of the different adipose tissue depots strongly contribute to define the complexity of adipocytokines network. Understanding those complex interactions may allow determining new potential biomarkers of CV risk and potential therapeutic targets.

The Role of Adipocytokines in Coronary Atherosclerosis.

Aims Neutrophil gelatinase-associated lipocalin (NGAL) is an effector molecule of the innate immune system. One of its actions is the prolongation of matrix metalloproteinase-9 (MMP-9) activity by the formation of a degradation-resistant NGAL/MMP-9 complex. We studied NGAL in human atherosclerotic lesions and we examined whether NGAL could act as a target for molecular imaging of atherosclerotic plaques.

Methods and results Increased levels of NGAL and the NGAL/MMP-9 complex were associated with high lipid content, high number of macrophages, high interleukin-6 (IL-6) and IL-8 levels, and low smooth muscle cell content in human atherosclerotic lesions obtained during carotid endarterectomy ( n = 122). Moreover, plaque levels of NGAL tended to be higher when intra-plaque haemorrhage (IPH) or luminal thrombus was present ( n = 77) than without the presence of IPH or thrombus ( n = 30). MMP-9 and -8 activities were strongly related to NGAL levels. The enhancement on magnetic resonance (MR) images of the abdominal aorta of ApoE−/−/eNOS−/− mice was observed at 72 h after injection of NGAL/24p3-targeted micelles. The specificity of these results was validated by histology, and co-localization of micelles, macrophages, and NGAL/24p3 was observed.

Conclusion NGAL is highly expressed in atheromatous human plaques and associated with increased MMP-9 activity. NGAL can be detected in murine atherosclerotic arteries using targeted high-resolution MR imaging. Therefore, we conclude that NGAL might serve as a novel imaging target for the detection of high-risk plaques.

/pdf/molecular-mri-of-murine-atherosclerotic-plaque-targeting-5fphya1c6z.pdf

Molecular MRI of murine atherosclerotic plaque targeting NGAL: a protein associated with unstable human plaque characteristics

Measurement of cardiac function is often performed in mice after, for example, a myocardial infarction. Cardiac MRI is often used because it is noninvasive and provides high temporal and spatial resolution for the left and right ventricle. In animal cardiac MRI, the quality of the required electrocardiogram signal is variable and sometimes deteriorates over time, especially with infarcted hearts or cardiac hypertrophy. Therefore, we compared the self-gated IntraGateFLASH method with a prospectively triggered FLASH (fast low-angle shot) method in mice with myocardial infarcts (n = 16) and in control mice (n = 21). Mice with a myocardial infarct and control mice were imaged in a vertical 9.4-T MR system. Images of contiguous 1-mm slices were acquired from apex to base with prospective and self-gated methods. Data were processed to calculate cardiac function parameters for the left and right ventricle. The signal-to-noise and contrast-to-noise ratios were calculated in mid-ventricular slices. The signal-to-noise and contrast-to-noise ratios of the self-gated data were higher than those of the prospectively gated data. Differences between the two gating methods in the cardiac function parameters for both left and right ventricle (e.g. end-diastolic volumes) did not exceed the inter-observer variability in control or myocardial infarcted mice. Both methods gave comparable results with regard to the cardiac function parameters in both healthy control mice and mice with myocardial infarcts. Moreover, the self-gated method provided better signal-to-noise and contrast-to-noise ratios when the acquisition time was equal. In conclusion, the self-gated method is suitable for routine use in cardiac MRI in mice with myocardial infarcts as well as in control mice, and obviates the need for electrocardiogram triggering and respiratory gating. In both gating methods, more than 10 frames per cardiac cycle are recommended. Copyright © 2010 John Wiley & Sons, Ltd.

Evaluation of infarcted murine heart function: comparison of prospectively triggered with self-gated MRI.

Negative MR contrast caused by USPIO uptake in lymph nodes may lead to false positive observations with in vivo visualization of murine atherosclerotic plaque.

Intra-plaque hemorrhage (IPH) and lipid core, characteristics of rupture prone carotid plaques, are often visualized in vivo with MRI using T1 weighted gradient and spin echo, respectively. Increasing magnetic field strength may help to identify IPH and lipid core better. As a proof of concept, automatic segmentation of plaque components was performed with the Mahalanobis distance (MD) measure derived from image contrast from multicontrast MR images including inversion recovery spin echo and T1 weighted gradient echo with fat suppression. After MRI of nine formaldehyde-fixated autopsy specimens, the MDs and Euclidean Distances between plaque component intensities were calculated for each MR weighting. The distances from the carotid bifurcation and the size and shape of calcification spots were used as landmarks for coregistration of MRI and histology. MD between collagen/cell-rich area and IPH was largest with inversion recovery spin echo (4.2/9.3, respectively), between collagen/cell-rich area/foam cells and lipid core with T1 weighted gradient echo with fat suppression (26.9/38.2/4.6, respectively). The accuracy of detection of IPH, cell-rich area, and collagen increased when the MD classifier was used compared with the Euclidean Distance classifier. The enhanced conspicuity of lipid core and IPH in human carotid artery plaque, using ex vivo T1 weighted gradient echo with fat suppression and inversion recovery spin echo MRI and MD classifiers, demands further in vivo evaluation in patients. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc.

Evaluation of multicontrast MRI including fat suppression and inversion recovery spin echo for identification of intra-plaque hemorrhage and lipid core in human carotid plaque using the mahalanobis distance measure.

Kees W.A. van de Kolk

Papers

Molecular MRI of murine atherosclerotic plaque targeting NGAL: a protein associated with unstable human plaque characteristics

Evaluation of infarcted murine heart function: comparison of prospectively triggered with self-gated MRI.

Negative MR contrast caused by USPIO uptake in lymph nodes may lead to false positive observations with in vivo visualization of murine atherosclerotic plaque.

Evaluation of multicontrast MRI including fat suppression and inversion recovery spin echo for identification of intra-plaque hemorrhage and lipid core in human carotid plaque using the mahalanobis distance measure.