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High Density Lipoprotein Cholesterol Increasing Therapy: The Unmet Cardiovascular Need.

Cimmino G, Ciccarelli G, Morello A, Ciccarelli M, Golino P - Transl Med UniSa (2014)

Bottom Line: Despite aggressive strategies are now available to reduce LDL-cholesterol, the risk of cardiovascular events in patients with coronary artery disease remains substantial.Several preclinical and clinical studies have shown that drug therapy ultimately leads to a regression of the angiographic lesions but also results in a reduction in cardiovascular events.As a result, HDL-based therapeutic interventions that maintain or enhance HDL functionality, such as improving its main property, the reverse cholesterol transport, require closer investigation.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, Italy;

ABSTRACT
Despite aggressive strategies are now available to reduce LDL-cholesterol, the risk of cardiovascular events in patients with coronary artery disease remains substantial. Several preclinical and clinical studies have shown that drug therapy ultimately leads to a regression of the angiographic lesions but also results in a reduction in cardiovascular events. The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein (CEPT) inhibitors, torcetrapib and dalcetrapib, has led to considerable doubt about the value of the current strategy to raise high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These clinical results, as well as animal studies, have revealed the complexity of HDL metabolism, assessing a more important role of functional quality compared to circulating quantity of HDL. As a result, HDL-based therapeutic interventions that maintain or enhance HDL functionality, such as improving its main property, the reverse cholesterol transport, require closer investigation. In this review, we will discuss HDL metabolism and function, clinical-trial data available for HDL-raising agents, and potential strategies for future HDL-based therapies.

No MeSH data available.


Related in: MedlinePlus

HDL formation: HDL particles start out as apolipoproteins produced by the liver, called apoAI. Precursor molecules are released in HDL called pre-B-HDL, incorporating small quantities of cholesterol and lipids, especially phospholipids (PL). ABC proteins (ATP-Binging Cassette Transports) transport various molecules across extra- and intra-cellular membranes. Cholesterol from non-hepatic peripheral tissues is transferred to HDL by the ABCA1. ABCG1 and ABCG4 are necessary for the further lipidation. These receptors are required for spherical particles HDL formation. The free cholesterol (FC) is converted to cholesteryl esters (CE) by the enzyme LCAT (lecithin-cholesterol acyltransferase).
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f1-tm-12-29: HDL formation: HDL particles start out as apolipoproteins produced by the liver, called apoAI. Precursor molecules are released in HDL called pre-B-HDL, incorporating small quantities of cholesterol and lipids, especially phospholipids (PL). ABC proteins (ATP-Binging Cassette Transports) transport various molecules across extra- and intra-cellular membranes. Cholesterol from non-hepatic peripheral tissues is transferred to HDL by the ABCA1. ABCG1 and ABCG4 are necessary for the further lipidation. These receptors are required for spherical particles HDL formation. The free cholesterol (FC) is converted to cholesteryl esters (CE) by the enzyme LCAT (lecithin-cholesterol acyltransferase).

Mentions: Although the atheroprotective properties of HDL-C have not been directly compared, it is likely that RCT plays a crucial role in these anti-atherogenic effects [22]. The RCT hypothesis proposes that HDL-C accepts cholesterol from the periphery, such as arterial wall cells, and deliver it to the liver for excretion via the bile salts. In 1990 the pioneering work of Badimon et al. [23] employed HDL-C as a therapeutic agent: it was the first preclinical evidence that plaque regression is feasible, showing that HDL-C infusion promotes regression of pre-existing lesions in a rabbit model of atherosclerosis. Other HDL-C elevating interventions corroborated this finding in animals [18] and in humans [15, 19]. The life cycle of HDL begins with apolipoprotein A-I (ApoA-I) being synthesized by the liver and, after interaction with hepatic ATP-binding cassette transporter 1 (ABCA1), is secreted into plasma as lipid-poor ApoA-I [14, 22]. The maturation process starts by acquisition of cholesterol and phospholipids (PLs) via ABCA1-mediated efflux from the liver and the transfer of cholesterol, PLs, and apolipoproteins from chylomicrons and very low-density lipoproteins (VLDL) during lipoprotein-lipase-mediated lipolysis to form nascent pre-β-HDLs [13]. Additional cholesterol and PLs are acquired from cells in extrahepatic tissues via ABCA1-mediated efflux, progressively generating more cholesterol-enriched particles. The enzyme lecithin-cholesterol acyl transferase (LCAT), carried on HDLs, esterifies the free cholesterol (FC) to cholesteryl ester (CE), which migrate to the core of the HDL-particle to form mature HDLs that can acquire additional lipid via ABCG1 and SR-BI-mediated efflux [13, 14, 22] (Figure 1). Thus, pharmacological modulation of any of the key players in RCT may be of great importance for cholesterol accumulation and/or removal, ultimately modifying the atherosclerotic process.


High Density Lipoprotein Cholesterol Increasing Therapy: The Unmet Cardiovascular Need.

Cimmino G, Ciccarelli G, Morello A, Ciccarelli M, Golino P - Transl Med UniSa (2014)

HDL formation: HDL particles start out as apolipoproteins produced by the liver, called apoAI. Precursor molecules are released in HDL called pre-B-HDL, incorporating small quantities of cholesterol and lipids, especially phospholipids (PL). ABC proteins (ATP-Binging Cassette Transports) transport various molecules across extra- and intra-cellular membranes. Cholesterol from non-hepatic peripheral tissues is transferred to HDL by the ABCA1. ABCG1 and ABCG4 are necessary for the further lipidation. These receptors are required for spherical particles HDL formation. The free cholesterol (FC) is converted to cholesteryl esters (CE) by the enzyme LCAT (lecithin-cholesterol acyltransferase).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4592041&req=5

f1-tm-12-29: HDL formation: HDL particles start out as apolipoproteins produced by the liver, called apoAI. Precursor molecules are released in HDL called pre-B-HDL, incorporating small quantities of cholesterol and lipids, especially phospholipids (PL). ABC proteins (ATP-Binging Cassette Transports) transport various molecules across extra- and intra-cellular membranes. Cholesterol from non-hepatic peripheral tissues is transferred to HDL by the ABCA1. ABCG1 and ABCG4 are necessary for the further lipidation. These receptors are required for spherical particles HDL formation. The free cholesterol (FC) is converted to cholesteryl esters (CE) by the enzyme LCAT (lecithin-cholesterol acyltransferase).
Mentions: Although the atheroprotective properties of HDL-C have not been directly compared, it is likely that RCT plays a crucial role in these anti-atherogenic effects [22]. The RCT hypothesis proposes that HDL-C accepts cholesterol from the periphery, such as arterial wall cells, and deliver it to the liver for excretion via the bile salts. In 1990 the pioneering work of Badimon et al. [23] employed HDL-C as a therapeutic agent: it was the first preclinical evidence that plaque regression is feasible, showing that HDL-C infusion promotes regression of pre-existing lesions in a rabbit model of atherosclerosis. Other HDL-C elevating interventions corroborated this finding in animals [18] and in humans [15, 19]. The life cycle of HDL begins with apolipoprotein A-I (ApoA-I) being synthesized by the liver and, after interaction with hepatic ATP-binding cassette transporter 1 (ABCA1), is secreted into plasma as lipid-poor ApoA-I [14, 22]. The maturation process starts by acquisition of cholesterol and phospholipids (PLs) via ABCA1-mediated efflux from the liver and the transfer of cholesterol, PLs, and apolipoproteins from chylomicrons and very low-density lipoproteins (VLDL) during lipoprotein-lipase-mediated lipolysis to form nascent pre-β-HDLs [13]. Additional cholesterol and PLs are acquired from cells in extrahepatic tissues via ABCA1-mediated efflux, progressively generating more cholesterol-enriched particles. The enzyme lecithin-cholesterol acyl transferase (LCAT), carried on HDLs, esterifies the free cholesterol (FC) to cholesteryl ester (CE), which migrate to the core of the HDL-particle to form mature HDLs that can acquire additional lipid via ABCG1 and SR-BI-mediated efflux [13, 14, 22] (Figure 1). Thus, pharmacological modulation of any of the key players in RCT may be of great importance for cholesterol accumulation and/or removal, ultimately modifying the atherosclerotic process.

Bottom Line: Despite aggressive strategies are now available to reduce LDL-cholesterol, the risk of cardiovascular events in patients with coronary artery disease remains substantial.Several preclinical and clinical studies have shown that drug therapy ultimately leads to a regression of the angiographic lesions but also results in a reduction in cardiovascular events.As a result, HDL-based therapeutic interventions that maintain or enhance HDL functionality, such as improving its main property, the reverse cholesterol transport, require closer investigation.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, Italy;

ABSTRACT
Despite aggressive strategies are now available to reduce LDL-cholesterol, the risk of cardiovascular events in patients with coronary artery disease remains substantial. Several preclinical and clinical studies have shown that drug therapy ultimately leads to a regression of the angiographic lesions but also results in a reduction in cardiovascular events. The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein (CEPT) inhibitors, torcetrapib and dalcetrapib, has led to considerable doubt about the value of the current strategy to raise high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These clinical results, as well as animal studies, have revealed the complexity of HDL metabolism, assessing a more important role of functional quality compared to circulating quantity of HDL. As a result, HDL-based therapeutic interventions that maintain or enhance HDL functionality, such as improving its main property, the reverse cholesterol transport, require closer investigation. In this review, we will discuss HDL metabolism and function, clinical-trial data available for HDL-raising agents, and potential strategies for future HDL-based therapies.

No MeSH data available.


Related in: MedlinePlus