HDL and Reverse Cholesterol Transport

Circulation Research, Journal Year: 2019, Volume and Issue: 124(10), P. 1505 - 1518

Published: May 9, 2019

Cardiovascular disease, with atherosclerosis as the major underlying factor, remains leading cause of death worldwide. It is well established that cholesterol ester-enriched foam cells are hallmark atherosclerotic plaques. Multiple lines evidence support enhancing cell efflux by HDL (high-density lipoprotein) particles, first step reverse transport (RCT), a promising antiatherogenic strategy. Yet, excitement towards therapeutic potential manipulating RCT for treatment cardiovascular disease has faded because lack association between risk and what was typically measured in intervention trials, namely cholesterol, which an inconsistent relationship to function RCT. In this review, we will summarize some reasons inconsistency, update mechanisms RCT, highlight conditions impaired or contributes vascular disease. On balance, still argues further research better understand how functionality develop prevention strategies reduce

Language: Английский

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MicroRNA-mediated regulation of glucose and lipid metabolism

Nature Reviews Molecular Cell Biology, Journal Year: 2021, Volume and Issue: 22(6), P. 425 - 438

Published: March 26, 2021

Language: Английский

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Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Aug. 2, 2022

Abstract Disturbed cholesterol homeostasis plays critical roles in the development of multiple diseases, such as cardiovascular diseases (CVD), neurodegenerative and cancers, particularly CVD which accumulation lipids (mainly cholesteryl esters) within macrophage/foam cells underneath endothelial layer drives formation atherosclerotic lesions eventually. More more studies have shown that lowering level, especially low-density lipoprotein protects system prevents events effectively. Maintaining is determined by biosynthesis, uptake, efflux, transport, storage, utilization, and/or excretion. All processes should be precisely controlled regulatory pathways. Based on regulation homeostasis, many interventions been developed to lower inhibiting biosynthesis uptake or enhancing utilization Herein, we summarize historical review research events, current understandings molecular pathways playing key regulating cholesterol-lowering clinics preclinical well new targets their clinical advances. importantly, discuss benefits those for treatment including obesity, diabetes, nonalcoholic fatty liver disease, cancer, osteoporosis virus infection.

Language: Английский

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Non-coding RNAs in cardiovascular cell biology and atherosclerosis

Cardiovascular Research, Journal Year: 2019, Volume and Issue: 115(12), P. 1732 - 1756

Published: Aug. 5, 2019

Atherosclerosis underlies the predominant number of cardiovascular diseases and remains a leading cause morbidity mortality worldwide. The development, progression formation clinically relevant atherosclerotic plaques involves interaction distinct over-lapping mechanisms which dictate roles actions multiple resident recruited cell types including endothelial cells, vascular smooth muscle monocyte/macrophages. discovery non-coding RNAs (ncRNAs) microRNAs, long RNAs, circular their identification as key mechanistic regulators mRNA protein expression has piqued interest in potential contribution to atherosclerosis. Accruing evidence revealed ncRNAs regulate pivotal cellular molecular processes during all stages atherosclerosis invasion, growth, survival; uptake efflux lipids, release pro- anti-inflammatory intermediaries, proteolytic balance. profile within lesions circulation have been determined with aim identifying individual or clusters may be viable therapeutic targets alongside deployment biomarkers plaque progression. Consequently, numerous vivo studies convened determine effects moderating function select well-characterized animal models Together, clinicopathological findings elucidated multifaceted frequently divergent impose both directly indirectly on From these findings' novel strategies discovered pave way for further translational possibly taken forward clinical application.

Language: Английский

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Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 31, 2024

Abstract The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate system, macrophages play an essential initial inflammatory that occurs following injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, diverse phenotypes and phenotypic alterations strongly associate with distinct types severity diseases, including coronary heart disease, valvular myocarditis, cardiomyopathy, failure, atherosclerosis aneurysm, which underscores importance investigating macrophage regulatory mechanisms within context specific diseases. Besides, recent strides single-cell sequencing technologies have revealed heterogeneity, cell–cell interactions, downstream therapeutic targets at higher resolution, brings new perspectives into macrophage-mediated potential Remarkably, myocardial fibrosis, prevalent characteristic most cardiac remains formidable clinical challenge, necessitating profound investigation impact on fibrosis In this review, we systematically summarize functional plasticity diseases unprecedented insights introduced by technologies, focus different causes characteristics especially relationship between inflammation (myocardial infarction, pressure overload, dilated diabetic cardiomyopathy aging) vascular injury (atherosclerosis aneurysm). Finally, highlight preclinical/clinical targeting strategies translational implications.

Language: Английский

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Macrophage-based therapeutic approaches for cardiovascular diseases

Basic Research in Cardiology, Journal Year: 2024, Volume and Issue: 119(1), P. 1 - 33

Published: Jan. 3, 2024

Despite the advances in treatment options, cardiovascular disease (CVDs) remains leading cause of death over world. Chronic inflammatory response and irreversible fibrosis are main underlying pathophysiological causes progression CVDs. In recent decades, cardiac macrophages have been recognized as regulatory players development these complex conditions. Numerous approaches aimed at devised, to novel prospects for therapeutic interventions. Our review covers advancements macrophage-centric plans various pathologic conditions examines potential consequences obstacles employing macrophage-targeted techniques diseases.

Language: Английский

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Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance

Cell Reports, Journal Year: 2018, Volume and Issue: 22(8), P. 2133 - 2145

Published: Feb. 1, 2018

While therapeutic modulation of miRNAs provides a promising approach for numerous diseases, the promiscuous nature raises concern over detrimental off-target effects. miR-33 has emerged as likely target treatment cardiovascular diseases. However, deleterious effects long-term anti-miR-33 therapies and predisposition miR-33−/− mice to obesity metabolic dysfunction exemplify possible pitfalls miRNA-based therapies. Our work an in-depth characterization explores mechanisms by which loss promotes insulin resistance in key tissues. Contrary previous reports, our data do not support direct role SREBP-1-mediated lipid synthesis promoting these Alternatively, adipose tissue mice, we observe increased pre-adipocyte proliferation, enhanced uptake, impaired lipolysis. Moreover, demonstrate that driving force behind abnormalities is food intake, can be prevented pair feeding with wild-type animals.

Language: Английский

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Foam Cells as Therapeutic Targets in Atherosclerosis with a Focus on the Regulatory Roles of Non-Coding RNAs

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(5), P. 2529 - 2529

Published: March 3, 2021

Atherosclerosis is a major cause of human cardiovascular disease, which the leading mortality around world. Various physiological and pathological processes are involved, including chronic inflammation, dysregulation lipid metabolism, development an environment characterized by oxidative stress improper immune responses. Accordingly, expansion novel targets for treatment atherosclerosis necessary. In this study, we focus on role foam cells in atherosclerosis. The specific therapeutic goals associated with each stage formation will be considered. Processing metabolism cholesterol macrophage one main steps cell formation. Cholesterol processing involves uptake, esterification efflux, ultimately leads to equilibrium macrophage. Recently, many preclinical studies have appeared concerning non-encoding RNAs atherosclerotic lesions. Non-encoding RNAs, especially microRNAs, considered regulators affecting expression genes involved uptake (e.g., CD36 LOX1) (ACAT1) efflux (ABCA1, ABCG1) cholesterol. They also able regulate inflammatory pathways, produce cytokines mediate apoptosis. We reviewed important evidence their targeting atherosclerosis, special

Language: Английский

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Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling

Circulation, Journal Year: 2022, Volume and Issue: 147(5), P. 388 - 408

Published: Nov. 23, 2022

Background: Cross-talk between sterol metabolism and inflammatory pathways has been demonstrated to significantly affect the development of atherosclerosis. Cholesterol biosynthetic intermediates derivatives are increasingly recognized as key immune regulators macrophages in response innate activation lipid overloading. 25-Hydroxycholesterol (25-HC) is produced an oxidation product cholesterol by enzyme 25-hydroxylase (CH25H) belongs a family bioactive cells fluctuating levels activation. Despite major role 25-HC mediator adaptive responses, its contribution during progression atherosclerosis remains unclear. Methods: The were analyzed liquid chromatography-mass spectrometry, expression CH25H different macrophage populations human or mouse atherosclerotic plaques, respectively. effect on was bone marrow adoptive transfer from wild-type Ch25h –/– mice lethally irradiated Ldlr mice, followed Western diet feeding for 12 weeks. Lipidomic, transcriptomic analysis effects function signaling vitro lipid-loaded isolated Ch25h–/–;Ldlr–/– . secreted fibrous cap formation using smooth muscle cell lineage–tracing model, Myh11 ERT2CRE mT/mG;Ldlr , adoptively transferred with weeks feeding. Results: We found that accumulated coronary lesions macrophage-derived accelerated progression, promoting plaque instability through autocrine paracrine actions. amplified inhibited migration within plaque. intensified responses lipid-laden modifying pool accessible plasma membrane, which altered Toll-like receptor 4 signaling, promoted nuclear factor-κB–mediated proinflammatory gene expression, increased apoptosis susceptibility. These independent 25-HC–mediated modulation liver X SREBP (sterol regulatory element–binding protein) transcriptional activity. Conclusions: Production activated amplifies their phenotype, thus atherogenesis.

Language: Английский

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Targeted Suppression of miRNA-33 Using pHLIP Improves Atherosclerosis Regression

Circulation Research, Journal Year: 2022, Volume and Issue: 131(1), P. 77 - 90

Published: May 10, 2022

miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate expression of miRNAs in vivo and could be used to correct imbalance gene found human diseases such as obesity, metabolic syndrome, atherosclerosis. The efficacy current anti-miRNA technologies hindered by physiological cellular barriers delivery into targeted cells nature that allows one target an entire pathway may lead deleterious off-target effects. For these reasons, novel systems inhibit specific tissues will important for developing effective therapeutic strategies numerous including

Language: Английский

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