Background: The aim of this study is to compare the colonization, immunoglobulin (Ig) G response,... more Background: The aim of this study is to compare the colonization, immunoglobulin (Ig) G response, and alveolar bone loss in Aggregatibacter actinomycetemcomitans (Aa)–inoculated Fawn Hooded Hypertensive (FHH), Dahl Salt‐Sensitive (DSS), and Brown Norway (BN) rats.Methods: Each rat strain was divided into wild‐type Aa‐inoculated and non‐inoculated control groups. Blood taken at 12 weeks after inoculation was assessed for Aa‐specific IgG antibodies by an enzyme‐linked immunosorbent assay. Colonization was assessed 12 weeks postinoculation. Bone loss was estimated by measuring the distance from the cemento‐enamel junction (CEJ) to the alveolar bone crest (ABC) at 20 molar sites. Colonization and antibody levels were compared by using the Student t test. Diseased rats were defined as having two sites per quadrant with CEJ–ABC distances that were significantly greater than the control CEJ–ABC distances.Results: The Aa colonization of FHH rats was significantly higher than in other strain...
SARS-CoV-2 infection continues to cause increased morbidity and mortality, and due to the slow pa... more SARS-CoV-2 infection continues to cause increased morbidity and mortality, and due to the slow pace of vaccination COVID-19 will probably remain a global burden to health systems for a long time. Unfortunately, the necessary prevention and treatment strategies of COVID-19 have led to restriction measures that are hampering the routine care of common chronic metabolic conditions like hypercholesterolemia. It is of particular concern that during the acute phase of COVID-19, the control of pre-existing metabolic diseases tends to get worse which again increases the risk for complications and a poor outcome in these patients. A significant contributor to these complications is endothelial dysfunction which is associated with COVID-19. This Commentary will discuss the impact of COVID-19 on endothelial function particularly in patients with familial hypercholesterolemia (FH), a metabolic inherited disease known to in itself adversely affect endothelial function. There should be no hesitation to continue with statin therapy in severe hypercholesterolemic patients with COVID-19. We argue that in FH patients with COVID-19 the clinicians need even consider intensifying statin therapy as well as the addition of other lipid-lowering agents, such as proprotein convertase subtilisin/kexin type 9(PCSK9) inhibitors. In contrast to statins, the PCSK9 inhibitors lower lipoprotein(a) [Lp(a)] level, and, accordingly, these latter drugs need to be considered particularly in FH patients with an elevated level of Lp(a). This call applies to the in-hospital stay and also beyond. When considering that the vasculopathic effects of COVID-19 may persist, a longterm follow-up of individualized therapies in FH patients is warranted.
A recent meta-analysis of over 20,000 individuals showed that hospitalized COVID-19 patients with... more A recent meta-analysis of over 20,000 individuals showed that hospitalized COVID-19 patients with acute myocardial injury had more than fourfold higher mortality than those without such injury. Since the COVID-19 pandemic exacerbates already existing health inequalities, there is an urgent need to create measures to protect the most vulnerable patient groups, including those with a pre-existing increased risk of atherosclerotic cardiovascular disease (ASCVD). A typical example is familial hypercholesterolemia (FH), a common genetic disease affecting over 30 million individuals worldwide. If left untreated or undertreated, FH patients suffer from complications of premature ASCVD, such as acute coronary syndromes, resulting in acute myocardial injury/infarction. A recent population-based analysis provided strong evidence suggesting that COVID-19 poses an even higher risk for myocardial injury in FH patients. From the long-term preventive point of view, it is important to note that, in addition to the acutely elevated risk of myocardial injury, an elevated risk of ASCVD and its complications will persist after COVID-19. The decline in outpatient preventive care during the pandemic is likely to influence ASCVD risk and outcomes, particularly in highrisk patients, such as those with FH. This commentary aims to raise global awareness of the challenges that clinicians treating FH patients continue to face during the COVID-19 pandemic, with two low-to middle-income countries, South Africa and Brazil, serving as examples.
The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) ... more The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). Methods and results Of the theoretical estimated prevalence of 1/500 for heterozygous FH, ,1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
This review covers the current knowledge about plant stanol esters as a dietary treatment option ... more This review covers the current knowledge about plant stanol esters as a dietary treatment option for heterozygous familial hypercholesterolemia (he-FH) children. The current estimation of the prevalence of he-FH is about one out of 200–250 persons. In this autosomal dominant disease, the concentration of plasma low-density lipoprotein cholesterol (LDL-C) is strongly elevated since birth. Quantitative coronary angiography among he-FH patients has revealed that stenosing atherosclerotic plaques start to develop in he-FH males in their twenties and in he-FH females in their thirties, and that the magnitude of the plaque burden predicts future coronary events. The cumulative exposure of coronary arteries to the lifelong LDL-C elevation can be estimated by calculating the LDL-C burden (LDL-C level × years), and it can also be used to demonstrate the usefulness of dietary stanol ester treatment. Thus, when compared with untreated he-FH patients, the LDL-C burden of using statin from the a...
Approximately 35 million people worldwide suffer from heterozygous familial hypercholesterolaemia... more Approximately 35 million people worldwide suffer from heterozygous familial hypercholesterolaemia (HeFH), a condition characterized by genetically determined lifelong elevation of plasma low-density lipoprotein cholesterol (LDL-C). One in three of these patients also inherit an elevated plasma concentration of lipoprotein (a) [Lp(a)], a lipoprotein particle with atherogenic, inflammatory and prothrombotic properties. Accordingly, the combination of high plasma LDL-C and Lp(a) can markedly accelerate premature atherosclerotic cardiovascular disease (ASCVD). Neither statin nor ezetimibe lowers Lp(a), so that FH patients with high Lp(a) remain at high residual risk of ASCVD. PCSK9 monoclonal antibodies are indicated for HeFH patients not at guideline-recommended LDL-C target, but only lower Lp(a) concentration by 15-30%. Recent trials employing apo(a) antisense therapy show more potent (up to 90%) reductions in plasma Lp(a). The combination of PCSK9 inhibitor and apo(a) antisense therapy appears the optimal strategy for mitigating residual risk of ASCVD in HeFH patients with high Lp(a).
Arteriosclerosis, thrombosis, and vascular biology, 2016
Activation of the inflammasome pathway in macrophages results in the secretion of 2 potent proinf... more Activation of the inflammasome pathway in macrophages results in the secretion of 2 potent proinflammatory and proatherogenic cytokines, interleukin (IL)-1β, and IL-18. Atherosclerotic lesions are characterized by the presence of various endogenous activators of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, including cholesterol crystals and extracellular ATP. The aim of this study was to comprehensively characterize the expression of inflammasome pathway components and regulators in human atherosclerotic lesions. Twenty human coronary artery RNA samples from 10 explanted hearts were analyzed using an inflammasome pathway-focused quantitative polymerase chain reaction array. Advanced atherosclerotic plaques, when compared with early-to-intermediate lesions from the same coronary trees, displayed significant upregulation of 12 target genes, including the key inflammasome components apoptosis-associated speck-like protein containing a CARD domain, caspase-1, and IL-18...
Journal of Neuropathology & Experimental Neurology, 2014
Chronic inflammation contributes to remodeling, degeneration, and rupture of saccular intracrania... more Chronic inflammation contributes to remodeling, degeneration, and rupture of saccular intracranial artery aneurysms. Mast cells are important proinflammatory and proangiogenic cells in chronic inflammatory vascular diseases. Here we studied mast cells and neovascularization in 36 intraoperatively resected aneurysms using histology and immunohistochemistry and analyzed the clinical characteristics of the aneurysms according to bleeding status (unruptured vs ruptured). Among the 36 aneurysms, 9 contained mast cells (tryptasepositive cells) and 15 contained neovessels (CD34-and CD31-positive capillarylike structures). The density of neovessels was significantly higher in aneurysm walls containing mast cells than in walls not containing them. In particular, wall areas with abundant mast cells and neovessels also contained iron deposits, indicating damage of newly formed endothelium with ensuing microhemorrhages. Walls with the highest neovessel density and the greatest iron deposition also showed evidence of degeneration. Finally, none of the mast cellY containing aneurysms showed an intact luminal endothelium. Thus, mast cells may adversely affect both neovascular and luminal endothelia. The novel association of mast cells with neovessels and injurious microhemorrhages, as well as with luminal endothelial erosion, suggests that mast cells contribute to remodeling and degeneration of saccular intracranial artery aneurysms.
An increased activity of ATP-binding cassette transporter (ABC) A1 has been proposed as a mechani... more An increased activity of ATP-binding cassette transporter (ABC) A1 has been proposed as a mechanism underlying the hypocholesterolaemic effect of phytosterols. In the present study, ABCA1-deficient mice (ABCA1−/− mice) were used to examine the involvement of the ABCA1 in the reduction of intestinal cholesterol absorption in response to a phytosterol-enriched diet. A decrease in intestinal cholesterol absorption of 39 and 35% was observed after phytosterol treatment in ABCA1+/+ mice and in ABCA1−/− mice, respectively. No statistically significant changes in plasma lipoprotein profile or in intestinal ABCG5, ABCG8 and Niemann-Pick C1-Like 1 gene expression levels were found when phytosterol-treated ABCA1−/− mice and untreated ABCA1−/− mice were compared. We conclude that phytosterol inhibition of cholesterol absorption in mice is independent of ABCA1
In the arterial intima, macrophages become cholesterol-enriched foam cells and atherosclerotic le... more In the arterial intima, macrophages become cholesterol-enriched foam cells and atherosclerotic lesions are generated. This atherogenic process can be attenuated, prevented, or even reversed by HDL particles capable of initiating a multistep pathway known as the macrophage-specific reverse cholesterol transport. The macrophage-derived cholesterol released to HDL is taken up by the liver, secreted into the bile, and ultimately excreted in the feces. Importantly, the absorptive epithelial cells lining the lumen of the small intestine, the enterocytes, express several membrane-associated proteins which mediate the influx of luminal cholesterol and its subsequent efflux at their apical and basolateral sides. Moreover, generation of intestinal HDL and systemic effects of the gut microbiota recently revealed a direct link between the gut and the cholesterol cargo of peripheral macrophages. This review summarizes experimental evidence establishing that the reverse cholesterol transport pathway which initiates in macrophages is susceptible to modulation in the small intestine. We also describe 4 paths which govern cholesterol passage across the enterocyte and define a role for the gut in the regulation of reverse cholesterol transport. Understanding the concerted function of these paths may be useful when designing therapeutic strategies aimed at removing cholesterol from the foam cells which occupy atherosclerotic lesions.
circulation by several plasma factors, such as LCAT (3), cholesteryl ester transfer protein (CETP... more circulation by several plasma factors, such as LCAT (3), cholesteryl ester transfer protein (CETP) (4), phospholipid transfer protein (PLTP) (5), hepatic lipase, and endothelial lipase (6). Such physiological HDL remodeling can lead to destabilization of HDL structure, and in some cases also to the release of lipid-free/lipid-poor apoA-I from the particles and to particle fusion (7). Similarly, serum opacity factor (8) has been found to destabilize HDL particles with ensuing fusogenic formation of larger particles and concomitant release of lipid-free/lipid-poor apoA-I. Thus, generation of larger HDL particles coupled with the release of apoA-I appears to be a seminal characteristic of circulating HDL particles when exposed to various factors involved in their physiological remodeling. The ability of HDL to remove excess cholesterol from macrophages in the arterial intima, i.e., their ability to initiate the macrophage-specifi c reverse cholesterol transport pathway, is a key anti-atherogenic action of HDL. The various subclasses of HDL particles have distinct abilities to stimulate cellular cholesterol effl ux, the mature spherical ␣-migrating HDL particles preferring ABCG1-mediated and the lipidpoor pre -migrating apoA-I preferring ABCA1-mediated cholesterol effl ux (9). Importantly, the ability of HDL to remove cholesterol from macrophage foam cells may be compromised when HDL particles are modifi ed by enzymatic or nonenzymatic processes such as oxidation, glycosylation, nitrosylation/chlorination, or by proteolysis (10). Acidic pH of the extracellular fl uid is a common characteristic of infl ammatory tissue sites (11, 12) and, importantly, it has also been observed in human atherosclerotic lesions (13). Accordingly, circulating HDL particles entering such Abstract HDL particles may enter atherosclerotic lesions having an acidic intimal fl uid. Therefore, we investigated whether acidic pH would affect their structural and functional properties. For this purpose, HDL 2 and HDL 3 subfractions were incubated for various periods of time at different pH values ranging from 5.5 to 7.5, after which their protein and lipid compositions, size, structure, and cholesterol effl ux capacity were analyzed. Incubation of either subfraction at acidic pH induced unfolding of apolipoproteins, which was followed by release of lipid-poor apoA-I and ensuing fusion of the HDL particles. The acidic pH-modifi ed HDL particles exhibited an enhanced ability to promote cholesterol effl ux from cholesterol-laden primary human macrophages. Importantly, treatment of the acidic pH-modifi ed HDL with the mast cell-derived protease chymase completely depleted the newly generated lipidpoor apoA-I, and prevented the acidic pH-dependent increase in cholesterol effl ux. The above-found pH-dependent structural and functional changes were stronger in HDL 3 than in HDL 2. Spontaneous acidic pH-induced remodeling of mature spherical HDL particles increases HDL-induced cholesterol effl ux from macrophage foam cells, and therefore may have atheroprotective effects.
Electronegative LDL (LDL(-)) is a minor subfraction of modified LDL present in plasma. Among its ... more Electronegative LDL (LDL(-)) is a minor subfraction of modified LDL present in plasma. Among its atherogenic characteristics, low affinity to the LDL receptor and high binding to arterial proteoglycans (PGs) could be related to abnormalities in the conformation of its main protein, apolipoprotein B-100 (apoB-100). In the current study, we have performed an immunochemical analysis using monoclonal antibody (mAb) probes to analyze the conformation of apoB-100 in LDL(-). The study, performed with 28 anti-apoB-100 mAbs, showed that major differences of apoB-100 immunoreactivity between native LDL and LDL(-) concentrate in both terminal extremes. The mAbs Bsol 10, Bsol 14 (which recognize the amino-terminal region), Bsol 2, and Bsol 7 (carboxyl-terminal region) showed increased immunoreactivity in LDL(-), suggesting that both terminal extremes are more accessible in LDL(-) than in native LDL. The analysis of in vitro-modified LDLs, including LDL lipolyzed with sphingomyelinase (SMase-LDL...
Background: The aim of this study is to compare the colonization, immunoglobulin (Ig) G response,... more Background: The aim of this study is to compare the colonization, immunoglobulin (Ig) G response, and alveolar bone loss in Aggregatibacter actinomycetemcomitans (Aa)–inoculated Fawn Hooded Hypertensive (FHH), Dahl Salt‐Sensitive (DSS), and Brown Norway (BN) rats.Methods: Each rat strain was divided into wild‐type Aa‐inoculated and non‐inoculated control groups. Blood taken at 12 weeks after inoculation was assessed for Aa‐specific IgG antibodies by an enzyme‐linked immunosorbent assay. Colonization was assessed 12 weeks postinoculation. Bone loss was estimated by measuring the distance from the cemento‐enamel junction (CEJ) to the alveolar bone crest (ABC) at 20 molar sites. Colonization and antibody levels were compared by using the Student t test. Diseased rats were defined as having two sites per quadrant with CEJ–ABC distances that were significantly greater than the control CEJ–ABC distances.Results: The Aa colonization of FHH rats was significantly higher than in other strain...
SARS-CoV-2 infection continues to cause increased morbidity and mortality, and due to the slow pa... more SARS-CoV-2 infection continues to cause increased morbidity and mortality, and due to the slow pace of vaccination COVID-19 will probably remain a global burden to health systems for a long time. Unfortunately, the necessary prevention and treatment strategies of COVID-19 have led to restriction measures that are hampering the routine care of common chronic metabolic conditions like hypercholesterolemia. It is of particular concern that during the acute phase of COVID-19, the control of pre-existing metabolic diseases tends to get worse which again increases the risk for complications and a poor outcome in these patients. A significant contributor to these complications is endothelial dysfunction which is associated with COVID-19. This Commentary will discuss the impact of COVID-19 on endothelial function particularly in patients with familial hypercholesterolemia (FH), a metabolic inherited disease known to in itself adversely affect endothelial function. There should be no hesitation to continue with statin therapy in severe hypercholesterolemic patients with COVID-19. We argue that in FH patients with COVID-19 the clinicians need even consider intensifying statin therapy as well as the addition of other lipid-lowering agents, such as proprotein convertase subtilisin/kexin type 9(PCSK9) inhibitors. In contrast to statins, the PCSK9 inhibitors lower lipoprotein(a) [Lp(a)] level, and, accordingly, these latter drugs need to be considered particularly in FH patients with an elevated level of Lp(a). This call applies to the in-hospital stay and also beyond. When considering that the vasculopathic effects of COVID-19 may persist, a longterm follow-up of individualized therapies in FH patients is warranted.
A recent meta-analysis of over 20,000 individuals showed that hospitalized COVID-19 patients with... more A recent meta-analysis of over 20,000 individuals showed that hospitalized COVID-19 patients with acute myocardial injury had more than fourfold higher mortality than those without such injury. Since the COVID-19 pandemic exacerbates already existing health inequalities, there is an urgent need to create measures to protect the most vulnerable patient groups, including those with a pre-existing increased risk of atherosclerotic cardiovascular disease (ASCVD). A typical example is familial hypercholesterolemia (FH), a common genetic disease affecting over 30 million individuals worldwide. If left untreated or undertreated, FH patients suffer from complications of premature ASCVD, such as acute coronary syndromes, resulting in acute myocardial injury/infarction. A recent population-based analysis provided strong evidence suggesting that COVID-19 poses an even higher risk for myocardial injury in FH patients. From the long-term preventive point of view, it is important to note that, in addition to the acutely elevated risk of myocardial injury, an elevated risk of ASCVD and its complications will persist after COVID-19. The decline in outpatient preventive care during the pandemic is likely to influence ASCVD risk and outcomes, particularly in highrisk patients, such as those with FH. This commentary aims to raise global awareness of the challenges that clinicians treating FH patients continue to face during the COVID-19 pandemic, with two low-to middle-income countries, South Africa and Brazil, serving as examples.
The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) ... more The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). Methods and results Of the theoretical estimated prevalence of 1/500 for heterozygous FH, ,1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
This review covers the current knowledge about plant stanol esters as a dietary treatment option ... more This review covers the current knowledge about plant stanol esters as a dietary treatment option for heterozygous familial hypercholesterolemia (he-FH) children. The current estimation of the prevalence of he-FH is about one out of 200–250 persons. In this autosomal dominant disease, the concentration of plasma low-density lipoprotein cholesterol (LDL-C) is strongly elevated since birth. Quantitative coronary angiography among he-FH patients has revealed that stenosing atherosclerotic plaques start to develop in he-FH males in their twenties and in he-FH females in their thirties, and that the magnitude of the plaque burden predicts future coronary events. The cumulative exposure of coronary arteries to the lifelong LDL-C elevation can be estimated by calculating the LDL-C burden (LDL-C level × years), and it can also be used to demonstrate the usefulness of dietary stanol ester treatment. Thus, when compared with untreated he-FH patients, the LDL-C burden of using statin from the a...
Approximately 35 million people worldwide suffer from heterozygous familial hypercholesterolaemia... more Approximately 35 million people worldwide suffer from heterozygous familial hypercholesterolaemia (HeFH), a condition characterized by genetically determined lifelong elevation of plasma low-density lipoprotein cholesterol (LDL-C). One in three of these patients also inherit an elevated plasma concentration of lipoprotein (a) [Lp(a)], a lipoprotein particle with atherogenic, inflammatory and prothrombotic properties. Accordingly, the combination of high plasma LDL-C and Lp(a) can markedly accelerate premature atherosclerotic cardiovascular disease (ASCVD). Neither statin nor ezetimibe lowers Lp(a), so that FH patients with high Lp(a) remain at high residual risk of ASCVD. PCSK9 monoclonal antibodies are indicated for HeFH patients not at guideline-recommended LDL-C target, but only lower Lp(a) concentration by 15-30%. Recent trials employing apo(a) antisense therapy show more potent (up to 90%) reductions in plasma Lp(a). The combination of PCSK9 inhibitor and apo(a) antisense therapy appears the optimal strategy for mitigating residual risk of ASCVD in HeFH patients with high Lp(a).
Arteriosclerosis, thrombosis, and vascular biology, 2016
Activation of the inflammasome pathway in macrophages results in the secretion of 2 potent proinf... more Activation of the inflammasome pathway in macrophages results in the secretion of 2 potent proinflammatory and proatherogenic cytokines, interleukin (IL)-1β, and IL-18. Atherosclerotic lesions are characterized by the presence of various endogenous activators of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, including cholesterol crystals and extracellular ATP. The aim of this study was to comprehensively characterize the expression of inflammasome pathway components and regulators in human atherosclerotic lesions. Twenty human coronary artery RNA samples from 10 explanted hearts were analyzed using an inflammasome pathway-focused quantitative polymerase chain reaction array. Advanced atherosclerotic plaques, when compared with early-to-intermediate lesions from the same coronary trees, displayed significant upregulation of 12 target genes, including the key inflammasome components apoptosis-associated speck-like protein containing a CARD domain, caspase-1, and IL-18...
Journal of Neuropathology & Experimental Neurology, 2014
Chronic inflammation contributes to remodeling, degeneration, and rupture of saccular intracrania... more Chronic inflammation contributes to remodeling, degeneration, and rupture of saccular intracranial artery aneurysms. Mast cells are important proinflammatory and proangiogenic cells in chronic inflammatory vascular diseases. Here we studied mast cells and neovascularization in 36 intraoperatively resected aneurysms using histology and immunohistochemistry and analyzed the clinical characteristics of the aneurysms according to bleeding status (unruptured vs ruptured). Among the 36 aneurysms, 9 contained mast cells (tryptasepositive cells) and 15 contained neovessels (CD34-and CD31-positive capillarylike structures). The density of neovessels was significantly higher in aneurysm walls containing mast cells than in walls not containing them. In particular, wall areas with abundant mast cells and neovessels also contained iron deposits, indicating damage of newly formed endothelium with ensuing microhemorrhages. Walls with the highest neovessel density and the greatest iron deposition also showed evidence of degeneration. Finally, none of the mast cellY containing aneurysms showed an intact luminal endothelium. Thus, mast cells may adversely affect both neovascular and luminal endothelia. The novel association of mast cells with neovessels and injurious microhemorrhages, as well as with luminal endothelial erosion, suggests that mast cells contribute to remodeling and degeneration of saccular intracranial artery aneurysms.
An increased activity of ATP-binding cassette transporter (ABC) A1 has been proposed as a mechani... more An increased activity of ATP-binding cassette transporter (ABC) A1 has been proposed as a mechanism underlying the hypocholesterolaemic effect of phytosterols. In the present study, ABCA1-deficient mice (ABCA1−/− mice) were used to examine the involvement of the ABCA1 in the reduction of intestinal cholesterol absorption in response to a phytosterol-enriched diet. A decrease in intestinal cholesterol absorption of 39 and 35% was observed after phytosterol treatment in ABCA1+/+ mice and in ABCA1−/− mice, respectively. No statistically significant changes in plasma lipoprotein profile or in intestinal ABCG5, ABCG8 and Niemann-Pick C1-Like 1 gene expression levels were found when phytosterol-treated ABCA1−/− mice and untreated ABCA1−/− mice were compared. We conclude that phytosterol inhibition of cholesterol absorption in mice is independent of ABCA1
In the arterial intima, macrophages become cholesterol-enriched foam cells and atherosclerotic le... more In the arterial intima, macrophages become cholesterol-enriched foam cells and atherosclerotic lesions are generated. This atherogenic process can be attenuated, prevented, or even reversed by HDL particles capable of initiating a multistep pathway known as the macrophage-specific reverse cholesterol transport. The macrophage-derived cholesterol released to HDL is taken up by the liver, secreted into the bile, and ultimately excreted in the feces. Importantly, the absorptive epithelial cells lining the lumen of the small intestine, the enterocytes, express several membrane-associated proteins which mediate the influx of luminal cholesterol and its subsequent efflux at their apical and basolateral sides. Moreover, generation of intestinal HDL and systemic effects of the gut microbiota recently revealed a direct link between the gut and the cholesterol cargo of peripheral macrophages. This review summarizes experimental evidence establishing that the reverse cholesterol transport pathway which initiates in macrophages is susceptible to modulation in the small intestine. We also describe 4 paths which govern cholesterol passage across the enterocyte and define a role for the gut in the regulation of reverse cholesterol transport. Understanding the concerted function of these paths may be useful when designing therapeutic strategies aimed at removing cholesterol from the foam cells which occupy atherosclerotic lesions.
circulation by several plasma factors, such as LCAT (3), cholesteryl ester transfer protein (CETP... more circulation by several plasma factors, such as LCAT (3), cholesteryl ester transfer protein (CETP) (4), phospholipid transfer protein (PLTP) (5), hepatic lipase, and endothelial lipase (6). Such physiological HDL remodeling can lead to destabilization of HDL structure, and in some cases also to the release of lipid-free/lipid-poor apoA-I from the particles and to particle fusion (7). Similarly, serum opacity factor (8) has been found to destabilize HDL particles with ensuing fusogenic formation of larger particles and concomitant release of lipid-free/lipid-poor apoA-I. Thus, generation of larger HDL particles coupled with the release of apoA-I appears to be a seminal characteristic of circulating HDL particles when exposed to various factors involved in their physiological remodeling. The ability of HDL to remove excess cholesterol from macrophages in the arterial intima, i.e., their ability to initiate the macrophage-specifi c reverse cholesterol transport pathway, is a key anti-atherogenic action of HDL. The various subclasses of HDL particles have distinct abilities to stimulate cellular cholesterol effl ux, the mature spherical ␣-migrating HDL particles preferring ABCG1-mediated and the lipidpoor pre -migrating apoA-I preferring ABCA1-mediated cholesterol effl ux (9). Importantly, the ability of HDL to remove cholesterol from macrophage foam cells may be compromised when HDL particles are modifi ed by enzymatic or nonenzymatic processes such as oxidation, glycosylation, nitrosylation/chlorination, or by proteolysis (10). Acidic pH of the extracellular fl uid is a common characteristic of infl ammatory tissue sites (11, 12) and, importantly, it has also been observed in human atherosclerotic lesions (13). Accordingly, circulating HDL particles entering such Abstract HDL particles may enter atherosclerotic lesions having an acidic intimal fl uid. Therefore, we investigated whether acidic pH would affect their structural and functional properties. For this purpose, HDL 2 and HDL 3 subfractions were incubated for various periods of time at different pH values ranging from 5.5 to 7.5, after which their protein and lipid compositions, size, structure, and cholesterol effl ux capacity were analyzed. Incubation of either subfraction at acidic pH induced unfolding of apolipoproteins, which was followed by release of lipid-poor apoA-I and ensuing fusion of the HDL particles. The acidic pH-modifi ed HDL particles exhibited an enhanced ability to promote cholesterol effl ux from cholesterol-laden primary human macrophages. Importantly, treatment of the acidic pH-modifi ed HDL with the mast cell-derived protease chymase completely depleted the newly generated lipidpoor apoA-I, and prevented the acidic pH-dependent increase in cholesterol effl ux. The above-found pH-dependent structural and functional changes were stronger in HDL 3 than in HDL 2. Spontaneous acidic pH-induced remodeling of mature spherical HDL particles increases HDL-induced cholesterol effl ux from macrophage foam cells, and therefore may have atheroprotective effects.
Electronegative LDL (LDL(-)) is a minor subfraction of modified LDL present in plasma. Among its ... more Electronegative LDL (LDL(-)) is a minor subfraction of modified LDL present in plasma. Among its atherogenic characteristics, low affinity to the LDL receptor and high binding to arterial proteoglycans (PGs) could be related to abnormalities in the conformation of its main protein, apolipoprotein B-100 (apoB-100). In the current study, we have performed an immunochemical analysis using monoclonal antibody (mAb) probes to analyze the conformation of apoB-100 in LDL(-). The study, performed with 28 anti-apoB-100 mAbs, showed that major differences of apoB-100 immunoreactivity between native LDL and LDL(-) concentrate in both terminal extremes. The mAbs Bsol 10, Bsol 14 (which recognize the amino-terminal region), Bsol 2, and Bsol 7 (carboxyl-terminal region) showed increased immunoreactivity in LDL(-), suggesting that both terminal extremes are more accessible in LDL(-) than in native LDL. The analysis of in vitro-modified LDLs, including LDL lipolyzed with sphingomyelinase (SMase-LDL...
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