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Cells
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High Density Lipoproteins and Atherosclerosis
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High Density Lipoproteins and Atherosclerosis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 38110

Special Issue Editor

Prof. Dr. Alberico L. Catapano

E-Mail Website
Guest Editor
1. Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy
2. IRCCS Multimedica Hospital, 20099 Milan, Italy
Interests: atherosclerosis; dyslipidemias; cardiovascular disease; immunity; genetics; diabetes; lipoproteins; pharmacology; biochemistry; cardiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Epidemiological studies have shown an inverse correlation between high-density lipoprotein cholesterol (HDL-C) levels and the risk of cardiovascular disease, suggesting that increasing HDL-C levels would be beneficial. However, this assumption has been questioned by the failure of clinical trials testing HDL-C-raising therapies as well as the observations from Mendelian randomization studies showing that polymorphisms mainly or solely associated with increased HDL-C levels did not decrease the risk of myocardial infarction. These observations led to a shift in the focus from HDL-C levels toward HDL functional properties.

This Special Issue of Cells aims to discuss the relevance of HDL function in light of the most recent observations that suggest a higher risk of mortality and infection in subjects with extremely high HDL-C levels, and to deepen the knowledge of HDL’s role beyond its classical role in reverse cholesterol transport.

Prof. Alberico L. Catapano
Guest Editor

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Keywords

  • HDL
  • HDL-C
  • HDL functionality
  • atherosclerosis
  • reverse cholesterol transport
  • genetics

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Published Papers (7 papers)

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Review

17 pages, 785 KiB  
Review
HDL in Atherosclerotic Cardiovascular Disease: In Search of a Role
by Manuela Casula, Ornella Colpani, Sining Xie, Alberico L. Catapano and Andrea Baragetti
Cells 2021, 10(8), 1869; https://doi.org/10.3390/cells10081869 - 23 Jul 2021
Cited by 67 | Viewed by 6366
Abstract
For a long time, high-density lipoprotein cholesterol (HDL-C) has been regarded as a cardiovascular disease (CVD) protective factor. Recently, several epidemiological studies, while confirming low plasma levels of HDL-C as an established predictive biomarker for atherosclerotic CVD, indicated that not only people at [...] Read more.
For a long time, high-density lipoprotein cholesterol (HDL-C) has been regarded as a cardiovascular disease (CVD) protective factor. Recently, several epidemiological studies, while confirming low plasma levels of HDL-C as an established predictive biomarker for atherosclerotic CVD, indicated that not only people at the lowest levels but also those with high HDL-C levels are at increased risk of cardiovascular (CV) mortality. This “U-shaped” association has further fueled the discussion on the pathophysiological role of HDL in CVD. In fact, genetic studies, Mendelian randomization approaches, and clinical trials have challenged the notion of HDL-C levels being causally linked to CVD protection, independent of the cholesterol content in low-density lipoproteins (LDL-C). These findings have prompted a reconsideration of the biological functions of HDL that can be summarized with the word “HDL functionality”, a term that embraces the many reported biological activities beyond the so-called reverse cholesterol transport, to explain this lack of correlation between HDL levels and CVD. All these aspects are summarized and critically discussed in this review, in an attempt to provide a background scenario for the “HDL story”, a lipoprotein still in search of a role. Full article
(This article belongs to the Special Issue High Density Lipoproteins and Atherosclerosis)
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17 pages, 4562 KiB  
Review
HDL in Immune-Inflammatory Responses: Implications beyond Cardiovascular Diseases
by Fabrizia Bonacina, Angela Pirillo, Alberico L. Catapano and Giuseppe D. Norata
Cells 2021, 10(5), 1061; https://doi.org/10.3390/cells10051061 - 29 Apr 2021
Cited by 38 | Viewed by 4623
Abstract
High density lipoproteins (HDL) are heterogeneous particles composed by a vast array of proteins and lipids, mostly recognized for their cardiovascular (CV) protective effects. However, evidences from basic to clinical research have contributed to depict a role of HDL in the modulation of [...] Read more.
High density lipoproteins (HDL) are heterogeneous particles composed by a vast array of proteins and lipids, mostly recognized for their cardiovascular (CV) protective effects. However, evidences from basic to clinical research have contributed to depict a role of HDL in the modulation of immune-inflammatory response thus paving the road to investigate their involvement in other diseases beyond those related to the CV system. HDL-C levels and HDL composition are indeed altered in patients with autoimmune diseases and usually associated to disease severity. At molecular levels, HDL have been shown to modulate the anti-inflammatory potential of endothelial cells and, by controlling the amount of cellular cholesterol, to interfere with the signaling through plasma membrane lipid rafts in immune cells. These findings, coupled to observations acquired from subjects carrying mutations in genes related to HDL system, have helped to elucidate the contribution of HDL beyond cholesterol efflux thus posing HDL-based therapies as a compelling interventional approach to limit the inflammatory burden of immune-inflammatory diseases. Full article
(This article belongs to the Special Issue High Density Lipoproteins and Atherosclerosis)
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Figure 1

27 pages, 2057 KiB  
Review
The Endothelium Is Both a Target and a Barrier of HDL’s Protective Functions
by Jérôme Robert, Elena Osto and Arnold von Eckardstein
Cells 2021, 10(5), 1041; https://doi.org/10.3390/cells10051041 - 28 Apr 2021
Cited by 47 | Viewed by 5740
Abstract
The vascular endothelium serves as a barrier between the intravascular and extravascular compartments. High-density lipoproteins (HDL) have two kinds of interactions with this barrier. First, bloodborne HDL must pass the endothelium to access extravascular tissues, for example the arterial wall or the brain, [...] Read more.
The vascular endothelium serves as a barrier between the intravascular and extravascular compartments. High-density lipoproteins (HDL) have two kinds of interactions with this barrier. First, bloodborne HDL must pass the endothelium to access extravascular tissues, for example the arterial wall or the brain, to mediate cholesterol efflux from macrophages and other cells or exert other functions. To complete reverse cholesterol transport, HDL must even pass the endothelium a second time to re-enter circulation via the lymphatics. Transendothelial HDL transport is a regulated process involving scavenger receptor SR-BI, endothelial lipase, and ATP binding cassette transporters A1 and G1. Second, HDL helps to maintain the integrity of the endothelial barrier by (i) promoting junction closure as well as (ii) repair by stimulating the proliferation and migration of endothelial cells and their progenitor cells, and by preventing (iii) loss of glycocalix, (iv) apoptosis, as well as (v) transmigration of inflammatory cells. Additional vasoprotective functions of HDL include (vi) the induction of nitric oxide (NO) production and (vii) the inhibition of reactive oxygen species (ROS) production. These vasoprotective functions are exerted by the interactions of HDL particles with SR-BI as well as specific agonists carried by HDL, notably sphingosine-1-phophate (S1P), with their specific cellular counterparts, e.g., S1P receptors. Various diseases modify the protein and lipid composition and thereby the endothelial functionality of HDL. Thorough understanding of the structure–function relationships underlying the multiple interactions of HDL with endothelial cells is expected to elucidate new targets and strategies for the treatment or prevention of various diseases. Full article
(This article belongs to the Special Issue High Density Lipoproteins and Atherosclerosis)
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16 pages, 427 KiB  
Review
High Density Lipoproteins and Diabetes
by Blake J. Cochran, Kwok-Leung Ong, Bikash Manandhar and Kerry-Anne Rye
Cells 2021, 10(4), 850; https://doi.org/10.3390/cells10040850 - 9 Apr 2021
Cited by 35 | Viewed by 4118
Abstract
Epidemiological studies have established that a high plasma high density lipoprotein cholesterol (HDL-C) level is associated with reduced cardiovascular risk. However, recent randomised clinical trials of interventions that increase HDL-C levels have failed to establish a causal basis for this relationship. This has [...] Read more.
Epidemiological studies have established that a high plasma high density lipoprotein cholesterol (HDL-C) level is associated with reduced cardiovascular risk. However, recent randomised clinical trials of interventions that increase HDL-C levels have failed to establish a causal basis for this relationship. This has led to a shift in HDL research efforts towards developing strategies that improve the cardioprotective functions of HDLs, rather than simply increasing HDL-C levels. These efforts are also leading to the discovery of novel HDL functions that are unrelated to cardiovascular disease. One of the most recently identified functions of HDLs is their potent antidiabetic properties. The antidiabetic functions of HDLs, and recent key advances in this area are the subject of this review. Given that all forms of diabetes are increasing at an alarming rate globally, there is a clear unmet need to identify and develop new approaches that will complement existing therapies and reduce disease progression as well as reverse established disease. Exploration of a potential role for HDLs and their constituent lipids and apolipoproteins in this area is clearly warranted. This review highlights focus areas that have yet to be investigated and potential strategies for exploiting the antidiabetic functions of HDLs. Full article
(This article belongs to the Special Issue High Density Lipoproteins and Atherosclerosis)
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12 pages, 717 KiB  
Review
High-Density Lipoproteins and the Kidney
by Arianna Strazzella, Alice Ossoli and Laura Calabresi
Cells 2021, 10(4), 764; https://doi.org/10.3390/cells10040764 - 31 Mar 2021
Cited by 20 | Viewed by 3787
Abstract
Dyslipidemia is a typical trait of patients with chronic kidney disease (CKD) and it is typically characterized by reduced high-density lipoprotein (HDL)-cholesterol(c) levels. The low HDL-c concentration is the only lipid alteration associated with the progression of renal disease in mild-to-moderate CKD patients. [...] Read more.
Dyslipidemia is a typical trait of patients with chronic kidney disease (CKD) and it is typically characterized by reduced high-density lipoprotein (HDL)-cholesterol(c) levels. The low HDL-c concentration is the only lipid alteration associated with the progression of renal disease in mild-to-moderate CKD patients. Plasma HDL levels are not only reduced but also characterized by alterations in composition and structure, which are responsible for the loss of atheroprotective functions, like the ability to promote cholesterol efflux from peripheral cells and antioxidant and anti-inflammatory proprieties. The interconnection between HDL and renal function is confirmed by the fact that genetic HDL defects can lead to kidney disease; in fact, mutations in apoA-I, apoE, apoL, and lecithin–cholesterol acyltransferase (LCAT) are associated with the development of renal damage. Genetic LCAT deficiency is the most emblematic case and represents a unique tool to evaluate the impact of alterations in the HDL system on the progression of renal disease. Lipid abnormalities detected in LCAT-deficient carriers mirror the ones observed in CKD patients, which indeed present an acquired LCAT deficiency. In this context, circulating LCAT levels predict CKD progression in individuals at early stages of renal dysfunction and in the general population. This review summarizes the main alterations of HDL in CKD, focusing on the latest update of acquired and genetic LCAT defects associated with the progression of renal disease. Full article
(This article belongs to the Special Issue High Density Lipoproteins and Atherosclerosis)
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Figure 1

18 pages, 1830 KiB  
Review
Apolipoprotein Mimetic Peptides: Potential New Therapies for Cardiovascular Diseases
by Anna Wolska, Mart Reimund, Denis O. Sviridov, Marcelo J. Amar and Alan T. Remaley
Cells 2021, 10(3), 597; https://doi.org/10.3390/cells10030597 - 8 Mar 2021
Cited by 32 | Viewed by 5147
Abstract
Since the seminal breakthrough of treating diabetic patients with insulin in the 1920s, there has been great interest in developing other proteins and their peptide mimetics as therapies for a wide variety of other medical disorders. Currently, there are at least 60 different [...] Read more.
Since the seminal breakthrough of treating diabetic patients with insulin in the 1920s, there has been great interest in developing other proteins and their peptide mimetics as therapies for a wide variety of other medical disorders. Currently, there are at least 60 different peptides that have been approved for human use and over 150 peptides that are in various stages of clinical development. Peptides mimetic of the major proteins on lipoproteins, namely apolipoproteins, have also been developed first as tools for understanding apolipoprotein structure and more recently as potential therapeutics. In this review, we discuss the biochemistry, peptide mimetics design and clinical trials for peptides based on apoA-I, apoE and apoC-II. We primarily focus on applications of peptide mimetics related to cardiovascular diseases. We conclude with a discussion on the limitations of peptides as therapeutic agents and the challenges that need to be overcome before apolipoprotein mimetic peptides can be developed into new drugs. Full article
(This article belongs to the Special Issue High Density Lipoproteins and Atherosclerosis)
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36 pages, 1108 KiB  
Review
High Density Lipoprotein Cholesterol Efflux Capacity and Atherosclerosis in Cardiovascular Disease: Pathophysiological Aspects and Pharmacological Perspectives
by Maria Pia Adorni, Nicoletta Ronda, Franco Bernini and Francesca Zimetti
Cells 2021, 10(3), 574; https://doi.org/10.3390/cells10030574 - 5 Mar 2021
Cited by 52 | Viewed by 7482
Abstract
Over the years, the relationship between high-density lipoprotein (HDL) and atherosclerosis, initially highlighted by the Framingham study, has been revealed to be extremely complex, due to the multiple HDL functions involved in atheroprotection. Among them, HDL cholesterol efflux capacity (CEC), the ability of [...] Read more.
Over the years, the relationship between high-density lipoprotein (HDL) and atherosclerosis, initially highlighted by the Framingham study, has been revealed to be extremely complex, due to the multiple HDL functions involved in atheroprotection. Among them, HDL cholesterol efflux capacity (CEC), the ability of HDL to promote cell cholesterol efflux from cells, has emerged as a better predictor of cardiovascular (CV) risk compared to merely plasma HDL-cholesterol (HDL-C) levels. HDL CEC is impaired in many genetic and pathological conditions associated to high CV risk such as dyslipidemia, chronic kidney disease, diabetes, inflammatory and autoimmune diseases, endocrine disorders, etc. The present review describes the current knowledge on HDL CEC modifications in these conditions, focusing on the most recent human studies and on genetic and pathophysiologic aspects. In addition, the most relevant strategies possibly modulating HDL CEC, including lifestyle modifications, as well as nutraceutical and pharmacological interventions, will be discussed. The objective of this review is to help understanding whether, from the current evidence, HDL CEC may be considered as a valid biomarker of CV risk and a potential pharmacological target for novel therapeutic approaches. Full article
(This article belongs to the Special Issue High Density Lipoproteins and Atherosclerosis)
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