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Biomedical subjects

Alan M Fogelman

Publications and source records attributed to Alan M Fogelman.

At least 19 recordsLinked to original sources
PubMed2007

Modifying the anti-inflammatory effects of high-density lipoprotein.

The anti-inflammatory effects of high-density lipoproteins (HDL) are well documented and include inhibition of low-density lipoprotein (LDL) oxidation, reduction of inflammatory cytokines and vascular leukocyte adhesion molecules, and participation in innate immunity. However, certain conditions, including coronary disease, diabetes mellitus, systemic inflammation, and a diet high in saturated fat, are associated with modification of HDL such that it paradoxically enhances LDL oxidation and/or vascular inflammation. Treatment with statins and/or apolipoprotein A1 mimetic peptides improves HDL's anti-inflammatory functions, and these as well as other medications may represent a novel pathway through which to target atherosclerosis.

Humans↗
PubMed2006

Paraoxonase-2 deficiency aggravates atherosclerosis in mice despite lower apolipoprotein-B-containing lipoproteins: anti-atherogenic role for paraoxonase-2.

Paraoxonases (PONs) are a family of proteins that may play a significant role in providing relief from both toxic environmental chemicals as well as physiological oxidative stress. Although the physiological roles of the PON family of proteins, PON1, PON2, and PON3, remain unknown, epidemiological, biochemical, and mouse genetic studies of PON1 suggest an anti-atherogenic function for paraoxonases. To determine whether PON2 plays a role in the development of atherosclerosis in vivo, we generated PON2-deficient mice. When challenged with a high fat, high cholesterol diet for 15 weeks, serum levels of high density lipoprotein cholesterol, triglycerides, and glucose were not significantly different between wild-type and PON2-deficient mice. In contrast, serum levels of very low density lipoprotein (VLDL)/low density lipoprotein (LDL) cholesterol were significantly lower (-32%) in PON2-deficient mice compared with wild-type mice. However, despite lower levels of VLDL/LDL cholesterol, mice deficient in PON2 developed significantly larger (2.7-fold) atherosclerotic lesions compared with their wild-type counterparts. Enhanced inflammatory properties of LDL, attenuated anti-atherogenic capacity of high density lipoprotein, and a heightened state of oxidative stress coupled with an exacerbated inflammatory response from PON2-deficient macrophages appear to be the main mechanisms behind the larger atherosclerotic lesions in PON2-deficient mice. These results demonstrate that PON2 plays a protective role in atherosclerosis.

Animals↗
PubMed2006

D-4F decreases brain arteriole inflammation and improves cognitive performance in LDL receptor-null mice on a Western diet.

LDL receptor-null mice on a Western diet (WD) have inflammation in large arteries and endothelial dysfunction in small arteries, which are improved with the apolipoprotein A-I mimetic D-4F. The role of hyperlipidemia in causing inflammation of very small vessels such as brain arterioles has not previously been studied. A WD caused a marked increase in the percent of brain arterioles with associated macrophages (microglia) (P < 0.01), which was reduced by oral D-4F but not by scrambled D-4F (ScD-4F; P < 0.01). D-4F (but not ScD-4F) reduced the percent of brain arterioles associated with CCL3/macrophage inflammatory protein-1alpha (P < 0.01) and CCL2/monocyte chemoattractant protein-1 (P < 0.001). A WD increased (P < 0.001) brain arteriole wall thickness and smooth muscle alpha-actin, which was reduced by D-4F but not by ScD-4F (P < 0.0001). There was no difference in plasma lipid levels, blood pressure, or arteriole lumen diameter with D-4F treatment. Cognitive performance in the T-maze continuous alternation task and in the Morris Water Maze was impaired by a WD and was significantly improved with D-4F but not ScD-4F (P < 0.05). We conclude that a WD induces brain arteriole inflammation and cognitive impairment that is ameliorated by oral D-4F without altering plasma lipids, blood pressure, or arteriole lumen size.

Actins↗
PubMed2006

Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis.

OBJECTIVE: Women with systemic lupus erythematosus (SLE) have a 7-50-fold increased risk of coronary artery disease (CAD). In the general population, oxidized low-density lipoprotein (ox-LDL) increases the risk for CAD. Normal high-density lipoproteins (HDLs) protect LDL from oxidation; proinflammatory HDLs do not. This study was undertaken to determine whether patients with SLE, who have chronic inflammation that causes oxidative damage, have more proinflammatory HDL and higher levels of ox-LDL, thus predisposing them to atherosclerosis. METHODS: One hundred fifty-four women with SLE, 48 women with rheumatoid arthritis (RA), and 72 healthy controls were studied. The ability of the patients' HDL to prevent oxidation of normal LDL was measured. Values >1.0 (the value assigned for LDL oxidation in the absence of HDL) after the addition of HDL indicated proinflammatory HDL. Plasma ox-LDL levels were measured as the amount of oxidation produced by the patient's LDL after the removal of HDL. RESULTS: SLE patients had more proinflammatory HDL (mean +/- SD score 1.02 +/- 0.57, versus 0.68 +/- 0.28 in controls [P < 0.0001] and 0.81 +/- 0.22 in RA patients [P = 0.001 versus SLE patients]). A higher proportion of SLE patients had proinflammatory HDL: 44.7% of SLE patients versus 4.1% of controls and 20.1% of RA patients had scores >1.0 (P < 0.006 between all groups). Levels of ox-LDL correlated with levels of proinflammatory HDL (r = 0.37, P < 0.001). SLE patients with CAD had significantly higher proinflammatory HDL scores than patients without CAD (P < 0.001). CONCLUSION: HDLs are proinflammatory in a significant proportion of SLE patients and are associated with elevated levels of ox-LDL. Abnormal HDLs impair the ability to prevent LDL oxidation and may predispose to atherosclerosis.

Adult↗
PubMed2006

High-density lipoprotein: is it always atheroprotective?

High-density lipoproteins (HDLs) are appropriately recognized for their many atheroprotective functions, including reverse cholesterol transport, as well as antioxidant, anti-inflammatory, and antithrombotic effects. Furthermore, the inverse relationship between HDL cholesterol and atherosclerosis is well documented in many populations. However, there is an increasing body of evidence that there are circumstances in which HDL may not be protective, and may in fact paradoxically promote vascular inflammation and oxidation of low-density lipoproteins. Recent studies have provided insight as to specific chemical modifications and structural changes within HDL associated with this phenotype. The presence of proinflammatory HDL coincides with conditions associated with chronic systemic inflammation, including atherosclerosis.

Anticholesteremic Agents↗
PubMed2006

Apolipoprotein A-I mimetic peptides and their role in atherosclerosis prevention.

The importance of apolipoprotein A-I (apoA-I) in atherosclerosis was established by testing in animal models, and its potential usefulness in humans has been confirmed in preliminary studies. ApoA-I is a large protein comprising 243 amino acids, which means that venous administration is necessary. In addition, manufacture of apoA-I is difficult and expensive. Research has, therefore, been directed towards finding smaller peptide mimetics that produce similar results to apoA-I, but that are easier to manufacture and administer. The earliest peptides mimicked some of the lipid-binding properties of apoA-I but did not prevent atherosclerosis in mice. A detailed study of the physical-chemical characteristics of these peptides led to the realization that the hydrophobic region of the peptide was critical in determining bioactivity. A potent peptide, 4F, which was synthesized wholly from D-amino acids, could be given orally. Use of 4F significantly improved the function of HDL in mice and monkeys. When 4F was administered in combination with a statin, lesion size and macrophage content were reduced in mice with atherosclerosis, and lesions regressed in older mice. Vasoreactivity and endothelial sloughing were also improved in other rodent studies. Early human clinical trials are now being carried out on 4F. Here, we review the studies on apoA-I mimetic peptides that have been carried out so far.

Animals↗
PubMed2006

Mechanisms of disease: proatherogenic HDL--an evolving field.

It is well known that, in large populations, HDL-cholesterol levels are inversely related to the risk of atherosclerotic clinical events; however, in an individual, the predictive value of an HDL-cholesterol level is far from perfect. As a result, other HDL-associated factors have been investigated, including the quality and function of HDL in contradistinction to the level of HDL-cholesterol. Regarding their quality, HDL particles are highly heterogeneous and contain varying levels of antioxidants or pro-oxidants, which results in variation in HDL function. It has been postulated that HDL functions to promote reverse cholesterol transport. Recent studies support this role for HDL but also indicate that HDL is a modulator of systemic inflammation. In the absence of inflammation, HDL has a complement of antioxidant enzymes that work to maintain an anti-inflammatory state. In the presence of systemic inflammation, these antioxidant enzymes can be inactivated and HDL can accumulate oxidized lipids and proteins that make it proinflammatory. Under these conditions the main protein of HDL, apolipoprotein A-I, can be modified by reactive oxygen species. This modification impairs the ability of HDL to promote cholesterol efflux by the ATP-binding cassette transporter A-1 pathway. Animal studies and small-scale human studies suggest that measures of the quality and novel functions of HDL might provide an improved means of identifying subjects at increased risk for atherosclerotic events, compared with the current practice of only measuring HDL-cholesterol levels. The quality and function of HDL are also attractive targets for emerging therapies.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2006

Synthetic peptides: managing lipid disorders.

PURPOSE OF REVIEW: Recent publications related to the potential use of synthetic peptides for the management of lipid disorders and their vascular complications are reviewed. RECENT FINDINGS: The potential use of synthetic peptides for the management of lipid disorders and their vascular complications has emerged in recent years. These peptides are models of apolipoproteins, but are much smaller in size than the apolipoproteins. Oral peptides that improve the antiinflammatory properties of HDLs have been shown to potently inhibit atherosclerosis in mouse models. Injection of a peptide with a class A amphipathic helix in a rat model of diabetes dramatically reduced endothelial sloughing and improved vasoreactivity. Injected synthetic peptides have also been described that dramatically lower plasma cholesterol and restore endothelial function in a rabbit model of familial hypercholesterolemia. These studies suggest the therapeutic potential for synthetic peptides in the management of lipid disorders and their vascular complications. SUMMARY: Synthetic peptides much smaller than exchangeable human plasma apolipoproteins but with physical and chemical characteristics similar to the plasma apolipoproteins have shown promise in the management of lipid disorders and their vascular complications in animal models. The initial success of these animal studies suggests that synthetic peptides have the potential to emerge as a new therapeutic class of agents in the management of patients with lipid disorders.

Animals↗
PubMed2006

Potential clinical utility of high-density lipoprotein-mimetic peptides.

PURPOSE OF REVIEW: To determine the potential clinical utility of high-density lipoprotein-mimetic peptides. RECENT FINDINGS: Oral administration of D-4F together with pravastatin caused lesion regression in old apoE null mice. Administration of D-4F to low-density lipoprotein receptor null mice fed a Western diet reduced the association of myeloperoxidase with apoA-I and reduced the 3-nitrotyrosine content of apoA-I. Oral D-4F improved arterial vasoreactivity independent of apoA-I. Mice genetically lacking apoA-I showed significant improvement in vasoreactivity but, in contrast to mice with apoA-I, did not demonstrate reduced arterial wall thickness after D-4F treatment. In a rat model of diabetes, D-4F administration induced heme oxygenase-1 and extracellular superoxide dismutase, prevented endothelial sloughing, and dramatically improved arterial vasoreactivity. A peptide with 10 D-amino acid residues taken from the sequence of apoJ rendered high-density lipoprotein anti-inflammatory in mice and monkeys, and dramatically reduced atherosclerosis in apoE null mice. Oral administration of tetrapeptides synthesized from either L-amino acids or D-amino acids rendered high-density lipoprotein anti-inflammatory in mice and monkeys, and reduced atherosclerosis in apoE null mice. SUMMARY: Peptides that sequester lipoprotein lipid hydroperoxides release a series of high-density lipoprotein-associated antioxidant enzymes such as paraoxonase from inhibition and protect apoA-I from oxidative damage that would impair cholesterol efflux.

Animals↗
PubMed2006

Oral amphipathic peptides as therapeutic agents.

Cholesterol can promote inflammation by its ability to stimulate the production of reactive oxygen species that result in the formation of pro-inflammatory oxidised phospholipids. High-density lipoproteins (HDLs) are part of the innate immune response and can be either pro- or anti-inflammatory independently of plasma HDL-cholesterol levels. During systemic inflammation as occurs with atherosclerosis, Apolipoprotein A-I can be altered, reducing its ability to promote reverse cholesterol transport and HDL can become pro-inflammatory. Amphipathic peptides with either a class A amphipathic helix (D-4F) or a class G* amphipathic helix (D-[113-122]apoJ), or even those that are too small to form a helix (KRES and FREL) have some similar characteristics. Their interaction with lipids leads to a reduction in lipoprotein-lipid hydroperoxides that releases HDL-associated antioxidant enzymes, such as paraoxonase, therefore providing antiatherosclerosis and anti-inflammatory activity. In addition, the peptide D-4F stimulates the formation and cycling of pre-beta HDL. These amphipathic peptides appear to have therapeutic potential as oral agents.

Administration, Oral↗
PubMed2005

High-density lipoprotein function recent advances.

Although high-density lipoproteins (HDL) possess many features that contribute to the association between elevated HDL cholesterol and protection from atherosclerosis, these lipoproteins may be modified in certain individuals and/or circumstances to become proinflammatory. The ability of HDL to inhibit or paradoxically to enhance vascular inflammation, lipid oxidation, plaque growth, and thrombosis reflects changes in specific enzyme and protein components. The anti-inflammatory and proinflammatory functional properties of HDL can now be assessed using cell-based and cell-free assays. Acute or chronic systemic inflammation and the metabolic syndrome appear to render HDL proinflammatory. In contrast, statins and experimental agents such as apolipoprotein A-1 mimetics render HDL more anti-inflammatory. Functional characterization of HDL is a promising method for enhanced assessment of cardiovascular risk and effectiveness of risk reduction.

Animals↗
PubMed2005

Oral small peptides render HDL antiinflammatory in mice and monkeys and reduce atherosclerosis in ApoE null mice.

A peptide containing only 4 amino acid residues (KRES) that is too small to form an amphipathic helix, reduced lipoprotein lipid hydroperoxides (LOOH), increased paraoxonase activity, increased plasma HDL-cholesterol levels, rendered HDL antiinflammatory, and reduced atherosclerosis in apoE null mice. KRES was orally effective when synthesized from either L or D-amino acids suggesting that peptide-protein interactions were not required. Remarkably, changing the order of 2 amino acids (from KRES to KERS) resulted in the loss of all biologic activity. Solubility in ethyl acetate and interaction with lipids, as determined by differential scanning calorimetry, indicated significant differences between KRES and KERS. Negative stain electron microscopy showed that KRES formed organized peptide-lipid structures whereas KERS did not. Another tetrapeptide FREL shared many of the physical-chemical properties of KRES and was biologically active in mice and monkeys when synthesized from either L- or D-amino acids. After oral administration KRES and FREL were found associated with HDL whereas KERS was not. We conclude that the ability of peptides to interact with lipids, remove LOOH and activate antioxidant enzymes associated with HDL determines their antiinflammatory and antiatherogenic properties regardless of their ability to form amphipathic helixes.

Animals↗
PubMed2005

An oral apoJ peptide renders HDL antiinflammatory in mice and monkeys and dramatically reduces atherosclerosis in apolipoprotein E-null mice.

OBJECTIVE: To determine the properties of a peptide synthesized from D-amino acids corresponding to residues 113 to 122 in apolipoprotein (apo) J. METHODS AND RESULTS: In contrast to D-4F, D- [113-122]apoJ showed minimal self-association and helicity in the absence of lipids. D-4F increased the concentration of apoA-I with pre-beta mobility in apoE-null mice whereas D- [113-122]apoJ did not. After an oral dose D- [113-122]apoJ more slowly associated with lipoproteins and was cleared from plasma much more slowly than D-4F. D- [113-122]apoJ significantly improved the ability of plasma to promote cholesterol efflux and improved high-density lipoprotein (HDL) inflammatory properties for up to 48 hours after a single oral dose in apoE-null mice, whereas scrambled D- [113-122]apoJ did not. Oral administration of 125 microg/mouse/d of D- [113-122]apoJ reduced atherosclerosis in apoE-null mice (70.2% reduction in aortic root sinus lesion area, P=4.3 x 10(-13); 70.5% reduction by en face analysis, P=1.5 x 10(-6)). In monkeys, oral D- [113-122]apoJ rapidly reduced lipoprotein lipid hydroperoxides (LOOH) and improved HDL inflammatory properties. Adding 250 ng/mL of D-[113-122]apoJ (but not scrambled D- [113-122]apoJ) to plasma in vitro reduced LOOH and increased paraoxonase activity. CONCLUSIONS: Oral D- [113-122]apoJ significantly improves HDL inflammatory properties in mice and monkeys and inhibits lesion formation in apoE-null mice.

Administration, Oral↗
PubMed2005

D-4F and statins synergize to render HDL antiinflammatory in mice and monkeys and cause lesion regression in old apolipoprotein E-null mice.

OBJECTIVE: We tested for synergy between pravastatin and D-4F by administering oral doses of each in combination that were predetermined to be ineffective when given as single agents. METHODS AND RESULTS: The combination significantly increased high-density lipoprotein (HDL)-cholesterol levels, apolipoprotein (apo)A-I levels, paraoxonase activity, rendered HDL antiinflammatory, prevented lesion formation in young (79% reduction in en face lesion area; P<0.0001) and caused regression of established lesions in old apoE null mice (ie, mice receiving the combination for 6 months had lesion areas that were smaller than those before the start of treatment (P=0.019 for en face lesion area; P=0.004 for aortic root sinus lesion area). After 6 months of treatment with the combination, en face lesion area was 38% of that in mice maintained on chow alone; P<0.00004) with a 22% reduction in macrophage content in the remaining lesions (P=0.001), indicating an overall reduction in macrophages of 79%. The combination increased intestinal apoA-I synthesis by 60% (P=0.011). In monkeys, the combination also rendered HDL antiinflammatory. CONCLUSIONS: These results suggest that the combination of a statin and an HDL-based therapy may be a particularly potent treatment strategy.

Age Factors↗
PubMed2005

Apolipoprotein A-I mimetic peptides.

Despite identical amino acid composition, differences in class A amphipathic helical peptides caused by differences in the order of amino acids on the hydrophobic face results in substantial differences in antiinflammatory properties. One of these peptides is an apolipoprotein A-I (apoA-I) mimetic, D-4F. When given orally to mice and monkeys, D-4F caused the formation of pre-beta high-density lipoprotein (HDL), improved HDL-mediated cholesterol efflux, reduced lipoprotein lipid hydroperoxides, increased paraoxonase activity, and converted HDL from pro-inflammatory to antiinflammatory. In apolipoprotein E (apoE)-null mice, D-4F increased reverse cholesterol transport from macrophages. Oral D-4F reduced atherosclerosis in apoE-null and low-density lipoprotein (LDL) receptor-null mice. In vitro when added to human plasma at nanomolar concentrations, D-4F caused the formation of pre-beta HDL, reduced lipoprotein lipid hydroperoxides, increased paraoxonase activity, and converted HDL from pro-inflammatory to antiinflammatory. Physical-chemical properties and the ability of various class A amphipathic helical peptides to activate lecithin cholesterol acyltransferase (LCAT) in vitro did not predict biologic activity in vivo. In contrast, the use of cultured human artery wall cells in evaluating these peptides was more predictive of their efficacy in vivo. We conclude that the antiinflammatory properties of different class A amphipathic helical peptides depends on subtle differences in the configuration of the hydrophobic face of the peptides, which determines the ability of the peptides to sequester inflammatory lipids. These differences appear to be too subtle to predict efficacy based on physical-chemical properties alone. However, understanding these physical-chemical properties provides an explanation for the mechanism of action of the active peptides.

Animals↗
PubMed2005

When pouring water on the fire makes it burn brighter.

Earlier work seems to suggest that overexpression of uncoupling protein 1 would be anti-inflammatory. However, new findings show that expression of uncoupling protein 1 in aortic smooth muscle cells of mice increases reactive oxygen species, activates the renin-angiotensin system, elevates blood pressure, and worsens atherosclerosis.

Angiotensins↗