Enzymatically modified LDL  atherosclerosis and beyond  paving the way to acceptance

Torzewski, Michael

doi:10.2741/4642

Cited by 12 publications

(21 citation statements)

References 86 publications

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“…These suggestions are supported by the fact that, in rabbits, the inhibition of plasma CRP did not affect the development of atherosclerosis (42). It has also been previously postulated that the deposition of CRP at the atherosclerotic lesions may be independent of the CRP levels in the circulation and that CRP-mediated lipoprotein removal likely underlies the regression of early lesions which occurs continuously throughout life and that CRP should be considered as an anti-atherosclerotic protein (10,13). A long-term goal should be the discovery and design of small-molecule compounds to aid endogenous native CRP in capturing atherogenic LDL, as proposed earlier (14,25).…”

Section: Discussionmentioning

confidence: 92%

“…Oxidized LDL (ox-LDL), enzymatically-modified LDL (E-LDL) and acetylated LDL (ac-LDL) are different forms of modified atherogenic LDL that are used in in vitro experiments ( 1 , 2 , 13 ). In the presence of Ca 2+ , native or recombinant wild-type (WT) CRP interacts with E-LDL due to the exposure of PCh groups on E-LDL, but does not interact with ox-LDL and ac-LDL ( 14 – 16 ).…”

Section: Introductionmentioning

confidence: 99%

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Conformationally Altered C-Reactive Protein Capable of Binding to Atherogenic Lipoproteins Reduces Atherosclerosis

et al. 2020

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The aim of this study was to test the hypothesis that C-reactive protein (CRP) protects against the development of atherosclerosis and that a conformational alteration of wild-type CRP is necessary for CRP to do so. Atherosclerosis is an inflammatory cardiovascular disease and CRP is a plasma protein produced by the liver in inflammatory states. The co-localization of CRP and low-density lipoproteins (LDL) at atherosclerotic lesions suggests a possible role of CRP in atherosclerosis. CRP binds to phosphocholine-containing molecules but does not interact with LDL unless the phosphocholine groups in LDL are exposed. However, CRP can bind to LDL, without the exposure of phosphocholine groups, if the native conformation of CRP is altered. Previously, we reported a CRP mutant, F66A/T76Y/E81A, generated by site-directed mutagenesis, that did not bind to phosphocholine. Unexpectedly, this mutant CRP, without any more conformational alteration, was found to bind to atherogenic LDL. We hypothesized that this CRP mutant, unlike wild-type CRP, could be anti-atherosclerotic and, accordingly, the effects of mutant CRP on atherosclerosis in atherosclerosis-prone LDL receptor-deficient mice were evaluated. Administration of mutant CRP into mice every other day for a few weeks slowed the progression of atherosclerosis. The size of atherosclerotic lesions in the aorta of mice treated with mutant CRP for 9 weeks was ∼40% smaller than the lesions in the aorta of untreated mice. Thus, mutant CRP conferred protection against atherosclerosis, providing a proof of concept that a local inflammation-induced structural change in wild-type CRP is a prerequisite for CRP to control the development of atherosclerosis.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Conformationally Altered C-Reactive Protein Capable of Binding to Atherogenic Lipoproteins Reduces Atherosclerosis

et al. 2020

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“…Atherosclerosis or CAVD develop if early lesions cannot be resolved and progress into chronically inflamed sites. The presence of excess LDL, and its modification in the damaged tissue, seems to be a crucial factor in the initiation of pathologic lesions [29].…”

Section: Endothelial Cellsmentioning

confidence: 99%

“…When it comes to LDL, the exact nature of modification and the local concentration further impact the generated response. The matter is actively debated and reviewed elsewhere [29]. In order to dissect the function of p38 MAPK activation in vascular SMCs, more studies are needed.…”

Section: Smooth Muscle Cellsmentioning

confidence: 99%

Role of p38 MAPK in Atherosclerosis and Aortic Valve Sclerosis

Reustle

Torzewski

2018

IJMS

Self Cite

130

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Atherosclerosis and aortic valve sclerosis are cardiovascular diseases with an increasing prevalence in western societies. Statins are widely applied in atherosclerosis therapy, whereas no pharmacological interventions are available for the treatment of aortic valve sclerosis. Therefore, valve replacement surgery to prevent acute heart failure is the only option for patients with severe aortic stenosis. Both atherosclerosis and aortic valve sclerosis are not simply the consequence of degenerative processes, but rather diseases driven by inflammatory processes in response to lipid-deposition in the blood vessel wall and the aortic valve, respectively. The p38 mitogen-activated protein kinase (MAPK) is involved in inflammatory signaling and activated in response to various intracellular and extracellular stimuli, including oxidative stress, cytokines, and growth factors, all of which are abundantly present in atherosclerotic and aortic valve sclerotic lesions. The responses generated by p38 MAPK signaling in different cell types present in the lesions are diverse and might support the progression of the diseases. This review summarizes experimental findings relating to p38 MAPK in atherosclerosis and aortic valve sclerosis and discusses potential functions of p38 MAPK in the diseases with the aim of clarifying its eligibility as a pharmacological target.

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“…Even when identical conditions are used to oxidize the LDL ex vivo , the products could differ significantly, depending on the fatty acid composition and antioxidant status of the starting LDL preparation. The diversity of oxidized LDL particles is reviewed by Levitan et al ( 58 ) and for enzyme modified LDL by Torzewski ( 59 ).…”

Section: Foam Cell Formation In Smcsmentioning

confidence: 99%

S100/RAGE-Mediated Inflammation and Modified Cholesterol Lipoproteins as Mediators of Osteoblastic Differentiation of Vascular Smooth Muscle Cells

Chellan

Sutton

Bowman

2018

Front. Cardiovasc. Med.

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Arterial calcification is a feature of atherosclerosis and shares many risk factors including diabetes, dyslipidemia, chronic kidney disease, hypertension, and age. Although there is overlap in risk factors, anti-atherosclerotic therapies, including statins, fail to reduce arterial, and aortic valve calcifications. This suggests that low density lipoprotein (LDL) may not be the main driver for aortic valve disease and arterial calcification. This review focuses on modified LDLs and their role in mediating foam cell formation in smooth muscle cells (SMCs), with special emphasis on enzyme modified non-oxidized LDL (ELDL). In vivo, ELDL represents one of the many forms of modified LDLs present in the atherosclerotic vessel. Phenotypic changes of macrophages and SMCs brought about by the uptake of modified LDLs overlap significantly in an atherosclerotic milieu, making it practically impossible to differentiate between the effects from oxidized LDL, ELDL, and other LDL modification. By studying in vitro-generated modifications of LDL, we were able to demonstrate marked differences in the transcriptome of human coronary artery SMCs (HCASMCs) upon uptake of ELDL, OxLDL, and native LDL, indicating that specific modifications of LDL in atherosclerotic plaques may determine the biology and functional consequences in vasculature. Enzyme-modified non-oxidized LDL (ELDL) induces calcification of SMCs and this is associated with reduced mRNA levels for genes protective for calcification (ENPP1, MGP) and upregulation of osteoblastic genes. A second focus of this review is on the synergy between hyperlipidemia and accelerated calcification In vivo in a mouse models with transgenic expression of human S100A12. We summarize mechanisms of S100A12/RAGE mediated vascular inflammation promoting vascular and valve calcification in vivo.

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Enzymatically modified LDL atherosclerosis and beyond paving the way to acceptance

Cited by 12 publications

References 86 publications

Conformationally Altered C-Reactive Protein Capable of Binding to Atherogenic Lipoproteins Reduces Atherosclerosis

Conformationally Altered C-Reactive Protein Capable of Binding to Atherogenic Lipoproteins Reduces Atherosclerosis

Role of p38 MAPK in Atherosclerosis and Aortic Valve Sclerosis

S100/RAGE-Mediated Inflammation and Modified Cholesterol Lipoproteins as Mediators of Osteoblastic Differentiation of Vascular Smooth Muscle Cells

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