NGAL and MMP-9/NGAL as biomarkers of plaque vulnerability and targets of statins in patients with carotid atherosclerosis

Eilenberg, Wolf; Stojković, Stefan; Kaider, Alexandra; Kozakowski, Nicolas; Domenig, Christoph; Burghuber, Christopher; Nanobachvili, Josif; Huber, Kurt; Klinger, Markus; Neumayer, Christoph; Huk, Ihor; Wojta, Johann; Demyanets, Svitlana

doi:10.1515/cclm-2017-0156

Cited by 43 publications

(42 citation statements)

References 36 publications

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“…In addition, we demonstrated that NGAL up-regulated the production of pro-inflammatory cytokines IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1 in these cells in vitro [23]. Moreover, NGAL may serve as potential circulating biomarker of plaque vulnerability in patients with CAS, as was shown by our group recently [24]. …”

Section: Introductionmentioning

confidence: 86%

Neutrophil gelatinase associated lipocalin (NGAL) is elevated in type 2 diabetics with carotid artery stenosis and reduced under metformin treatment

Eilenberg

Stojković

Piechota-Polańczyk

et al. 2017

Cardiovasc Diabetol

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BackgroundNeutrophil gelatinase-associated lipocalin (NGAL), an acute phase protein released by neutrophils, has been described as biomarker of inflammatory states. Type 2 diabetes mellitus (T2DM) is characterized by increased inflammation and an elevated risk for embolization of carotid artery stenosis (CAS). We aimed to explore the role of NGAL systemically and in plaques of diabetics undergoing carotid endarterectomy. Moreover, the potential anti-inflammatory effect of metformin on NGAL was addressed in diabetics.MethodsSerum NGAL and matrix metalloproteinase (MMP)-9/NGAL levels were measured in 136 patients (67 with T2DM vs. 69 non-diabetics) by specific ELISA. Endarterectomy samples were graded histologically according to the American Heart Association´s classification. NGAL mRNA expression was detected using RealTime-PCR in carotid endarterectomy specimens.ResultsSerum NGAL [median 107.4 ng/ml (quartiles: 75.2–145.0) vs. 64.4 (50.4 –81.3), p < 0.0001] and MMP-9/NGAL [41.5 ng/ml (20.8–63.9) vs. 27.6 (16.0–42.4), p = 0.017] were significantly elevated in diabetics compared to non-diabetics, as were leukocytes, neutrophils, C-reactive protein and fibrinogen (all p < 0.05). In patients with symptomatic and asymptomatic CAS diabetics had higher NGAL levels compared to non-diabetics [128.8 ng/ml (100.8–195.6) vs. 64.8 (48.9–82.2] and [101.6 ng/ml (70.1–125.3) vs. 63.8 (51.0–81.3), respectively, both p < 0.0001]. Presence of T2DM and type VI plaques (with surface defect, hemorrhage or thrombus) had a profound impact on NGAL levels (both p < 0.01) in multiple linear regression analysis. NGAL mRNA was detectable in 95% of analyzed carotid artery lesions of diabetics compared to 5% of non-diabetics (p < 0.0001). Accordingly, cerebral embolization was more frequent in diabetics (52.2% vs. 29%, p = 0.006). Metformin treatment was associated with decreased NGAL [60.7 ng/ml (51.9–69.2) vs. 121.7 (103.7–169.9), p < 0.0001] and MMP-9/NGAL [20.8 ng/ml (12.1–26.5) vs. 53.7 (27.4–73.4), p = 0.007] in diabetics and reduced leukocyte infiltration in carotid lesions of diabetics.ConclusionsHigher NGAL levels in serum and plaques are associated with T2DM in patients with CAS. Metformin significantly reduced the inflammatory burden including NGAL in diabetics. Early treatment of these patients may be recommended, as elevated NGAL levels were linked with vulnerable plaques prone for embolization.

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Section: Introductionmentioning

confidence: 86%

Neutrophil gelatinase associated lipocalin (NGAL) is elevated in type 2 diabetics with carotid artery stenosis and reduced under metformin treatment

Eilenberg

Stojković

Piechota-Polańczyk

et al. 2017

Cardiovasc Diabetol

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“…An increasing number of studies have suggested that MMPs are the foremost factors that degrade the ECM and cause the rupture of vulnerable plaques (37,38). MMPs are grouped into five types based on their structure and substrate specificity; these include collagenases (MMP-1, -8, -13 and -18), gelatinases (MMP-2 and -9), stromelysins (MMP-3, -7, -10, -11 and -12), membrane-type MMPs (MMP-14, -15, -16, -17, -24 and -25) and the other MMPs (39).…”

Section: Discussionmentioning

confidence: 99%

Specific matrix metalloproteinases and calcification factors are associated with the vulnerability of human carotid plaque

et al. 2018

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The rupture of atherosclerotic plaque provokes the majority of acute cerebrovascular events. Studies have demonstrated that various matrix metalloproteinases (MMPs) may promote atherosclerotic plaque progression and rupture. However, results have been incongruous and the mechanisms of this remain obscured. Therefore, in the current study, carotid plaques were characterized by assessing the levels of MMPs and calcification factors, and evaluating their association with plaque vulnerability. Human carotid plaques were obtained from carotid endarterectomies, and classified into stable and vulnerable groups by ultrasonography and histological analyses. The mRNA and protein levels of MMPs, vascular endothelial growth factor (VEGF), bone sialoprotein 2 (BSP) and osteopontin were investigated by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. Immunohistochemistry was used to localize MMP-2 and MMP-14 in stable and vulnerable plaques. The activation of various associated signaling pathways was also investigated using western blotting. The mRNA levels of MMP-2, -7, -9 and -14 were elevated in vulnerable plaques, among which expression of MMP-2 and -14 were the highest. Consistent with the mRNA levels, the protein levels of MMP-2 and -14 were also elevated. Immunohistochemistry also demonstrated positive staining of MMP-2 and MMP-14 in vulnerable plaques. Factors that indicate neovascularization and calcification, including VEGF and BSP, were concurrently elevated in vulnerable plaques. In addition, the protein levels of extracellular regulated kinase (ERK) and protein kinase C (PKC) were upregulated in vulnerable plaques. The current study provides novel insights into the MMP profiles of vulnerability plaques, and may assist in the development of novel methods for the diagnosis of plaque vulnerability and the prevention of plaque rupture.

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“…Данное взаимодействие способствует пролонгированному действию ММП-9 и повышенной ее активности, что, в свою очередь, разрушает бляшку, и является пусковым стимулом для каскада реакций коагуляции и тромбоза [17]. Показано, что у больных с нестабильными АСБ и острым инфарктом миокарда наблюдаются высокие уровни НЖАЛ, комплекса НЖАЛ и ММП-9 по сравнению с пациентами со стабильной ИБС [14][15][16].…”

Section: участие нф в атерогенезеunclassified

“…В зарубежной и отечественной литературе большое внимание уделяется изучению роли нейтрофильных гранулоцитов в атерогенезе [14][15][16][17][18]. Однако представленные в открытой печати сведения о роли НФ в патогенезе АС немногочисленны, фрагментарны и требуют проведения дополнительных исследований.…”

Section: Introductionunclassified

The role of neutrophils in the pathogenesis of atherosclerosis

Саранчина

Дутова

Килина

et al. 2018

Cardiovasc Ther Prev

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Atherosclerosis (AS) is one of the causes of cardiovascular disease. The formation of atherosclerotic lesions of the arteries is a long process, and clinical symptoms appear already at the stage of atherosclerotic plaque (ASB), which prevents blood flow and can cause coronary heart disease, as well as acute coronary syndrome. The study of atherosclerosis mechanisms at the subclinical level is relevant. This article provides a summary of current data on the structure and functions of neutrophils (NF) in physiological processes. Particular attention is paid to the participation of neutrophils in the damage and formation of vascular endothelial dysfunction. Discusses several mechanisms of involvement of neutrophils in atherogenesis: the production of reactive oxygen species, which cause direct endothelial damage; the synthesis of cytokines that trigger the migration of leukocytes in inflammation; the formation of protein complexes with cholesterol, contributing to their deposition in the vessels, and neutrophil traps, triggering destructivealterative reactions. Conflicts of interest: nothing to declare.Funding. The results were obtained in the framework of the state task № 17.9545.2017/BCh of the Ministry of education and science of Russia. Роль нейтрофилов в патогенезе атеросклерозаСаранчина Ю. В., Дутова С. В., Килина О. Ю., Ханарин Н. В., Кулакова Т. С. ФГБОУ ВО "Хакасский государственный университет им. Н. Ф. Катанова". Абакан, Россия Атеросклероз (АС) является одной из причин сердечно-сосудистых заболеваний. Формирование атеросклеротического поражения артерий -длительный процесс, а клинические симптомы проявляются уже на стадии атеросклеротической бляшки, которая стенозируя сосуд, препятствует кровотоку, и может вызвать ишемическую болезнь сердца, а также острый коронарный синдром. В связи с чем, изучение механизмов АС на субклиническом уровне является актуальным. В представленной статье приводятся обобщенные современные данные о строении и функциях нейтрофилов (НФ) в физиологических процессах. Особое внимание в обзоре уделено участию НФ в повреждении и формировании дисфункции эндотелия сосудов как одного из основных звеньев патогенеза АС. Обсуждается несколько возможных механизмов участия НФ в атерогенезе: продукция активных форм кислорода, вызывающих непосредственное повреждение эндотелия; синтез цитокинов, активирующих миграцию лейкоцитов в очаг воспаления; образование белковых комплексов с холестерином, способствующих их отложе-нию в сосудах, и формирование нейтрофильных ловушек, запускающих деструктивно-альтеративные реакции. Ключевые слова: нейтрофилы, атеросклероз, атеросклеротическая бляшка, нейтрофильные ловушки, нейтрофильная эластаза, нейтрофильный желатиназо-ассоциированный липокалин.Конфликт интересов: не заявлен.Финансирование. Результаты получены в рамках выполнения государственного задания № 17.9545.2017/БЧ Минобрнауки России.Кардиоваскулярная терапия и профилактика. 2018;17(6):110-116 http://dx.

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NGAL and MMP-9/NGAL as biomarkers of plaque vulnerability and targets of statins in patients with carotid atherosclerosis

Abstract: Circulating NGAL and MMP-9/NGAL are associated with plaque vulnerability in patients with carotid artery stenosis. Statin treatment could contribute to plaque stabilization by reducing circulating NGAL and MMP-9/NGAL levels.

Cited by 43 publications

References 36 publications

Neutrophil gelatinase associated lipocalin (NGAL) is elevated in type 2 diabetics with carotid artery stenosis and reduced under metformin treatment

Neutrophil gelatinase associated lipocalin (NGAL) is elevated in type 2 diabetics with carotid artery stenosis and reduced under metformin treatment

Specific matrix metalloproteinases and calcification factors are associated with the vulnerability of human carotid plaque

The role of neutrophils in the pathogenesis of atherosclerosis

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