High-Density Lipoprotein-Targeted Therapy and Apolipoprotein A-I Mimetic Peptides

Uehara, Yoshio; Chiesa, Giulia; Saku, Keijiro

doi:10.1253/circj.cj-15-0960

Cited by 23 publications

(26 citation statements)

References 70 publications

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“…7,222,223 In cell culture experiments these rHDL particles imitate several potentially anti-atherogenic effects of native HDL, notably the induction of cholesterol efflux from macrophage foam cells as well as the stimulation of nitric oxide production and the inhibition of VCAM-1 expression and apoptosis by endothelial cells. In animal models of atherosclerosis, infusion of rHDL prevented the development of atherosclerosis or even caused regression of atherosclerosis.…”

Section: Hdl Mimeticsmentioning

confidence: 99%

“…222,223 At least three formulations of rHDL have entered clinical development and have been applied to humans: -CSL111 and its successor CSL112 consist of native apoA-I and phosphatidylcholines isolated from human plasma and soybean, respectively. 7,222,223 In the ERASE trial of 186 patients with ACS 2 weeks before, four weekly infusions of 40 mg CSL111/kg body weight induced a reduction of coronary atheroma volume as assessed by intravascular ultrasound (IVUS), which was statistical significant compared to baseline but not compared to placebo. 224 The infusion of CSL111 was also found to improve endothelial dysfunction, platelet function, and glycaemia in patients with type 2 diabetes mellitus.…”

Section: Hdl Mimeticsmentioning

confidence: 99%

“…228 -ETC-215 which is now further developed as MDCO-216 contains the apoA-I(R173C)Milano variant and palmitoyloleylcholine. 7,222,223 Compared to wild-type apoA-I containing rHDL, rHDL with apoA-I(R173C)Milano showed more potent cholesterol efflux-stimulating as well as anti-inflammatory capacities. 232 Like rHDL containing wild type apoA-I, ETC-215 induced the regression of atherosclerosis in both rabbit and mouse models of atherosclerosis.…”

Section: Hdl Mimeticsmentioning

confidence: 99%

“…232 Like rHDL containing wild type apoA-I, ETC-215 induced the regression of atherosclerosis in both rabbit and mouse models of atherosclerosis. 7,222,223 In a phase 2 study of 57 patients, five weekly ETC-215 infusions two weeks after ACS caused significant regression of IVUSassessed total atheroma volume in coronary arteries compared to baseline. 233 Infusion of MDCO-216 into cynomolgous monkeys increased the capacity of plasma to induce cholesterol efflux via the ABCA1 pathway much more prominently than via the ABCG1 and SR-BI pathways, probably by displacing endogenous wild-type apoA-I from endogenous HDL and thereby enhancing the formation of prebeta1-HDL.…”

Section: Hdl Mimeticsmentioning

confidence: 99%

“…There are many examples of functions and dysfunctions that have been associated with different molecules within HDL. For example the ability of normal HDL to stimulate nitric oxide production in endothelial cells has been assigned to pure apoA-I/phospholipid complexes 222,223 as well as to minor constituents such as S1P. 20 Endothelial HDL dysfunction has been assigned to the loss of S1P, 119 oxidative modifications of apoA-I or phospholipids, 40 enrichment with SAA 65 or SDMA.…”

Section: Diagnostics and Biomarker Discoverymentioning

confidence: 99%

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Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

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Section: Hdl Mimeticsmentioning

confidence: 99%

Section: Hdl Mimeticsmentioning

confidence: 99%

Section: Hdl Mimeticsmentioning

confidence: 99%

Section: Hdl Mimeticsmentioning

confidence: 99%

Section: Diagnostics and Biomarker Discoverymentioning

confidence: 99%

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Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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HDL Mimetic Peptides

Chen

Liu

2022

HDL Metabolism and Diseases

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Mechanisms of foam cell formation in atherosclerosis

et al. 2017

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Low-density lipoprotein (LDL) and cholesterol homeostasis in the peripheral blood is maintained by specialized cells, such as macrophages. Macrophages express a variety of scavenger receptors (SR) that interact with lipoproteins, including SR-A1, CD36, and lectin-like oxLDL receptor-1 (LOX-1). These cells also have several cholesterol transporters, including ATP-binding cassette transporter ABCA1, ABCG1, and SR-BI, that are involved in reverse cholesterol transport. Lipids internalized by phagocytosis are transported to late endosomes/lysosomes, where lysosomal acid lipase (LAL) digests cholesteryl esters releasing free cholesterol. Free cholesterol in turn is processed by acetyl-CoA acetyltransferase (ACAT1), an enzyme that transforms cholesterol to cholesteryl esters. The endoplasmic reticulum serves as a depot for maintaining newly synthesized cholesteryl esters that can be processed by neutral cholesterol ester hydrolase (NCEH), which generates free cholesterol that can exit via cholesterol transporters. In atherosclerosis, pro-inflammatory stimuli upregulate expression of scavenger receptors, especially LOX-1, and downregulate expression of cholesterol transporters. ACAT1 is also increased, while NCEH expression is reduced. This results in deposition of free and esterified cholesterol in macrophages and generation of foam cells. Moreover, other cell types, such as endothelial (ECs) and vascular smooth muscle cells (VSMCs), can also become foam cells. In this review, we discuss known pathways of foam cell formation in atherosclerosis.

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High-Density Lipoprotein-Targeted Therapy and Apolipoprotein A-I Mimetic Peptides

Cited by 23 publications

References 70 publications

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

HDL Mimetic Peptides

Mechanisms of foam cell formation in atherosclerosis

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