Endothelial cell metabolism: A novel player in atherosclerosis? Basic principles and therapeutic opportunities

Pircher, Andreas; Treps, Lucas; Bodrug, Natalia; Carmeliet, Peter

doi:10.1016/j.atherosclerosis.2016.08.011

Cited by 65 publications

(51 citation statements)

References 154 publications

(166 reference statements)

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“…Warburg effect improves the dysfunction of endothelial cells (ECs) in atherosclerosis. The dysfunction of ECs leads to accumulation of lipids and formation of atherosclerotic plaque (Pircher, Treps, Bodrug, & Carmeliet, ). In formal ECs, the rate of aerobic glycolysis is significantly elevated, while the level of miR‐143 is relatively low.…”

Section: The Role Of Warburg Effect In Heart Diseasesmentioning

confidence: 99%

Involvement of the Warburg effect in non‐tumor diseases processes

Chen

Liu

et al. 2017

Journal Cellular Physiology

125

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Warburg effect, as an energy shift from mitochondrial oxidative phosphorylation to aerobic glycolysis, is extensively found in various cancers. Interestingly, increasing researchers show that Warburg effect plays a crucial role in non-tumor diseases. For instance, inhibition of Warburg effect can alleviate pulmonary vascular remodeling in the process of pulmonary hypertension (PH). Interference of Warburg effect improves mitochondrial function and cardiac function in the process of cardiac hypertrophy and heart failure. Additionally, the Warburg effect induces vascular smooth muscle cell proliferation and contributes to atherosclerosis. Warburg effect may also involve in axonal damage and neuronal death, which are related with multiple sclerosis. Furthermore, Warburg effect significantly promotes cell proliferation and cyst expansion in polycystic kidney disease (PKD). Besides, Warburg effect relieves amyloid β-mediated cell death in Alzheimer's disease. And Warburg effect also improves the mycobacterium tuberculosis infection. Finally, we also introduce some glycolytic agonists. This review focuses on the newest researches about the role of Warburg effect in non-tumor diseases, including PH, tuberculosis, idiopathic pulmonary fibrosis (IPF), failing heart, cardiac hypertrophy, atherosclerosis, Alzheimer's diseases, multiple sclerosis, and PKD. Obviously, Warburg effect may be a potential therapeutic target for those non-tumor diseases.

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Section: The Role Of Warburg Effect In Heart Diseasesmentioning

confidence: 99%

Involvement of the Warburg effect in non‐tumor diseases processes

Chen

Liu

et al. 2017

Journal Cellular Physiology

125

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“…Patients with T2DM are especially prone to inflammatory processes, which lead among others to endothelial dysfunction [7, 13, 14]. Pro-inflammatory cytokines [such as interleukins (IL-1, IL-6), and tumour necrosis factor (TNF)-α] as well as chemokines and adhesion molecules have been shown to contribute to vascular complications in T2DM [13, 15].…”

Section: Introductionmentioning

confidence: 99%

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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“…EC function is all but static and effective as a summation and processing of multiple stimuli by individual cells, often within close proximity along the same vessel segment. Signalling affecting EC behaviour often involves generating and responding to reactive oxygen species (ROS) , which can be generated by the EC themselves or by neighbouring cells, as a result of metabolic shifts, injury or damage, or an immune response . It has been shown that the ROS‐associated antioxidant machinery expressed in EC is unique to vessel type and location within the vascular tree and organ of origin , suggesting that tolerance to oxidative stress is tissue‐specific, and some EC are more responsive/susceptible to oxidative damage than others.…”

Section: Regulation and Regulators Of Ec Function In Different Tissuesmentioning

confidence: 99%

“…EC are the only cells continuously exposed to laminar flow, to which vessel diameter and blood fluidity need to be adjusted in order to maintain perfusion. Their ability to endure and resist shear stress relies on ROS and NO X signals, as well as epigenetic control . Versatility and flexibility are essential EC properties, such that periods of altered cardiac output are not mirrored by altered organ function.…”

Section: Regulation and Regulators Of Ec Function In Different Tissuesmentioning

confidence: 99%

“…However, within organs and tissues, local control of perfusion in specialized capillary networks often bypasses autonomic control and the flow rate is adjusted to the tissue environment. Importantly, local adjustments in blood flow in specific organs, as a result of changes in EC activation, can result in systemic effects . One could consider that local control in those instances indeed overtakes autonomic influence.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Endothelial cells and organ function: applications and implications of understanding unique and reciprocal remodelling

Reiterer

Branco

2019

The FEBS Journal

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The microvasculature is a heterogeneous, dynamic and versatile component of the systemic circulation, with a unique ability to locally self‐regulate and to respond to organ demand and environmental stimuli. Endothelial cells from different organs display considerable variation, but it is currently unclear to what extent functional properties of organ‐specific endothelial cells are intrinsic, acquired and/or reprogrammable. Vascular function is a fundamental pillar of homeostasis, and dysfunction results in systemic consequences for the organism. Additionally, vascular failure can occur downstream of organ disease or environmental stress, often driving an exacerbation of symptoms and pathologies originally independent of the local circulation. The understanding of the molecular mechanisms underlying endothelial physiology and metabolism holds the promise to inform and improve diagnosis, prognosis and treatment options for a myriad of conditions as unrelated as cancer, neurodegeneration or pulmonary hypertension, and likely everything in between, if we consider that also treatments for such conditions are primarily distributed via the bloodstream. However, studying endothelial function has its challenges: the origin, isolation, culture conditions and preconditioning stimuli make this an extremely variable cell type to study and difficult to source. Animal models exist but are neither trivial to generate, nor necessarily adequately translatable to human disease. In this article, we aim to illustrate the breadth of microvascular functions in different environments, highlighting current and pioneering studies that have advanced our insight into the importance of the integrity of this tissue, as well as the limitations posed by its heterogeneity and plasticity.

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Endothelial cell metabolism: A novel player in atherosclerosis? Basic principles and therapeutic opportunities

Cited by 65 publications

References 154 publications

Involvement of the Warburg effect in non‐tumor diseases processes

Involvement of the Warburg effect in non‐tumor diseases processes

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

Endothelial cells and organ function: applications and implications of understanding unique and reciprocal remodelling

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