Recombinant Apolipoprotein A-I
            <sub>Milano</sub>
            Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks

Chiesa, Giulia; Monteggia, E; Marchesi, Matteo; Lorenzon, Paolo; Laucello, M; Lorusso, Vito; Mario, Carlo Di; Karvouni, Evangelia; Newton, Roger S.; Bisgaier, Charles L.; Franceschini, Guido; Sirtori, Cesare R.

doi:10.1161/01.res.0000018422.31717.ee

Cited by 195 publications

(120 citation statements)

References 49 publications

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“…25,26,32 Because reverse cholesterol transport is controlled at several discrete steps by different protein regulators and receptors, CETP inhibition is only one of several potential approaches for augmenting reverse cholesterol transport 49,59 -63 (see the Table). 49,53,54,58,62,[63][64][65][66][67] In fact, the clinical efficacy of pharmacological CETP inhibition could be substantially influenced by both diet and drugs that alter CETP pharmacokinetics. For instance, body weight influences CETP activity.…”

Section: Extension To Human Investigationmentioning

confidence: 99%

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

2005

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Abstract-Reduced HDL cholesterol may be a risk factor comparable in importance to increased LDL cholesterol.Interventions that raise HDL are antiatherosclerotic, presumably through acceleration of reverse cholesterol transport and by antioxidant and antiinflammatory effects. In the hypercholesterolemic rabbit, HDL levels can be increased by Ͼ50% by inhibition of cholesteryl ester transfer protein (CETP), a molecule that plays a central role in HDL metabolism. This HDL-raising effect is antiatherosclerotic in moderately severe hyperlipidemia but appears to be ineffective in the presence of severe hypertriglyceridemia. In humans, mutations resulting in CETP inhibition have been associated with both reduced and increased risk of atherosclerosis. Proposed explanations for these apparently disparate observations are that the antiatherosclerotic effect of CETP inhibition varies with either the metabolic milieu or the degree of CETP inhibition. We now have pharmacological inhibitors of CETP that are capable of increasing HDL by as much as 50% to 100% in humans. The importance of this development is that reduced HDL is a risk factor independent of LDL and that these new agents alter HDL by a magnitude comparable to that of statins on LDL. Clinical trials, now beginning, will need to identify the patient subsets in which CETP inhibition may be more or less effective. Key Words: atherosclerosis Ⅲ cholesterol Ⅲ lipids Ⅲ metabolism Ⅲ statins A lthough lipid-lowering therapies now have the capability of reducing LDL cholesterol to levels recommended by the National Cholesterol Education Program (NCEP) guidelines in as many as 90% of treated patients, 1 the rate of cardiovascular events is reduced by only 20% to 35% in large, randomized trials. These data suggest that the LDL target set by NCEP guidelines may be too high. 1-5 Indeed, among patients with acute myocardial infarction, Ϸ15% have LDL levels Ͻ100 mg/dL on presentation.A complementary hypothesis is that there is a finite limit to the benefit of LDL lowering and that other non-LDL lipid risk factors must be managed for optimal outcomes. Indeed, epidemiological studies suggest that low HDL cholesterol may be a risk factor comparable in importance to high LDL and that the 2 risk factors are independent (Figure 1). 6,7 Although the mechanism by which HDL reduces the development of atherosclerosis has not been defined with certainty, acceleration of reverse cholesterol transport, antioxidant activity, and antiinflammatory action are likely to play central roles. 8 -10 In contrast to the ability of potent statins to reduce the level of LDL by Ͼ50%, however, no currently approved therapy increases HDL by a comparable magnitude. The most potent, currently available HDL-raising therapy is nicotinic acid. This therapy also has a multitude of other antiatherosclerotic effects on the levels of LDL and triglycerides, lipid oxidation, and endothelial function. 11 Combination therapy with a statin has been reported to increase HDL levels by Ϸ30% 12 and to decrease cardiac events...

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Section: Extension To Human Investigationmentioning

confidence: 99%

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

2005

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“…Among these mutants, intravenous injections of rHDL containing R173C-apoA-I (apoA-IMilano) have been shown to have potent regression activity in a human phase II clinical trial, although the mechanism by which this A point mutant of apolipoprotein A-I, V156K, exhibited potent anti-oxidant and anti-atherosclerotic activity in hypercholesterolemic C57BL/6 mice remedy was affected has yet to be clearly elucidated (Nissen et al, 2003). A series of in vivo studies with R173C-apoA-I resulted in improvements in the pharmaceutical potential of HDL-therapy, via the use of reconstituted HDL (rHDL) with apoA-I variants (Shah et al, 1998;Chiesa et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

A point mutant of apolipoprotein A-I, V156K, exhibited potent anti-oxidant and anti-atherosclerotic activity in hypercholesterolemic C57BL/6 mice

Cho

Park²,

Han³

et al. 2007

Exp Mol Med

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In our previous study, two point mutants of apolipoprotein A-I, designated V156K and A158E, revealed peculiar characteristics in their lipid-free and lipid-bound states. In order to determine the putative therapeutic potential of these mutants, several in vitro and in vivo evaluations were conducted. In the lipid-free state, V156K showed more profound antioxidant activity against LDL oxidation than did the wildtype (WT) or A158E variants in an in vitro assay. In the lipid-bound state, V156K-rHDL showed an enhanced cholesterol delivery activity to HepG2 cells in a time-dependent manner, as compared to WT-rHDL, A158E-rHDL, and R173C-rHDL. We assessed the physiological activities of the mutants in circulation, using hypercholesterolemic mice (C57BL6/J). Palmitoyloleoyl phosphatidylcholine (POPC)-rHDL preparations containing each of the apoA-I variants were injected into the mice at a dosage of 30 mg of apoA-I/kg of body weight. Forty eight hours after injection, the sera of the V156K-rHDL injected group showed the most potent antioxidant abilities in the ferric acid removal assay. The V156K-rHDL-or R173C-rHDL-injected mice showed no atherosclerotic lesions and manifested striking increases in their serum apo-E levels, as compared to the mice injected with WT-rHDL or A158E-rHDL. In conclusion, V156K-rHDL exhibited the most pronounced antioxidant activity and anti-atherosclerotic activity, both in vitro and in vivo. These results support the notion that HDL-therapy may prove beneficial due to its capacity to induce accelerated cholesterol excretion, as well as its enhanced antioxidant and anti-inflammatory effects and lesion regression effect.

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“…120 These studies highlight the ability of a single infusion of rHDL to raise plasma HDL and improve vascular reactivity. These studies, combined with the rapidity of antiatherosclerotic effects of infusing rHDL containing apoA-I Milano (an apoA-I variant that may have enhanced antiatherogenic properties 22 ) into rabbits 121 and humans, 122 raise the possibility that some of the noncholesterol transport functions of HDL may be of pathophysiological importance.…”

Section: Importance Of the Antiinflammatory Effects Of Hdl In Vivomentioning

confidence: 99%

Anti-Inflammatory Properties of HDL

Ansell

Navab

Watson

et al. 2004

Rev Endocr Metab Disord

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Abstract-There are several well-documented functions of high-density lipoprotein (HDL) that may explain the ability of these lipoproteins to protect against atherosclerosis. The best recognized of these is the ability of HDL to promote the efflux of cholesterol from cells. This process may minimize the accumulation of foam cells in the artery wall. However, HDL has additional properties that may also be antiatherogenic. For example, HDL is an effective antioxidants. The major proteins of HDL, apoA-I and apoA-II, as well as other proteins such as paraoxonase that cotransport with HDL in plasma, are well-known to have antioxidant properties. As a consequence, HDL has the capacity to inhibit the oxidative modification of low-density lipoprotein (LDL) in a process that reduces the atherogenicity of these lipoproteins. HDL also possesses other antiinflammatory properties. By virtue of their ability to inhibit the expression of adhesion molecules in endothelial cells, they reduce the recruitment of blood monocytes into the artery wall. These antioxidant and antiinflammatory properties of HDL may be as important as its cholesterol efflux function in terms of protecting against the development of atherosclerosis. Key Words: antiinflammatory Ⅲ antioxidant Ⅲ atherosclerosis Ⅲ high-density lipoprotein I n epidemiological studies, high plasma levels of highdensity lipoproteins (HDLs) protect against the development of atherosclerosis. 1,2 The precise mechanism is uncertain, although most likely it is the consequence of one or more of the reported actions of HDL. 3 The best known of these relates to the ability of HDL to promote the efflux of cholesterol from cells in the artery wall. 4 However, HDLs have additional functions, some of which may be unrelated to their role in plasma lipid transport. For example, they bind lipopolysaccharide, 5 stimulate endothelial cell movement, 6 inhibit the synthesis of plateletactivating factor by endothelial cells, 7 and protect erythrocytes against the generation of procoagulant activity. 8 HDLs stimulate prostacyclin synthesis by endothelial cells. 9 They also bind prostacyclin and thus prolong its half-life. 10 They reduce epidermal growth factor-induced DNA synthesis in vascular smooth muscle cells. 11 HDLs are antithrombotic. 12 They modulate endothelial function, 13 probably by stimulating endothelial nitric oxide (NO) production. 14 HDLs also possess antioxidant and antiinflammatory activities. 3,[15][16][17][18][19][20][21] The degree to which any or all of these nonlipid transport functions of HDL contribute to a protection against atherosclerosis is still uncertain, although evidence is mounting that at least some of them may be especially important.This review focuses on the antioxidant and antiinflammatory properties of HDL (Figure 1). It summarizes the role of oxidation and inflammation in atherogenesis and describes how these processes may be inhibited by HDL. It concludes with an assessment of the potential clinical importance of the antioxidant and antiinflammatory propert...

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Recombinant Apolipoprotein A-I _Milano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks

Cited by 195 publications

References 49 publications

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

A point mutant of apolipoprotein A-I, V156K, exhibited potent anti-oxidant and anti-atherosclerotic activity in hypercholesterolemic C57BL/6 mice

Anti-Inflammatory Properties of HDL

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Recombinant Apolipoprotein A-I Milano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks

Cited by 195 publications

References 49 publications

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

A point mutant of apolipoprotein A-I, V156K, exhibited potent anti-oxidant and anti-atherosclerotic activity in hypercholesterolemic C57BL/6 mice

Anti-Inflammatory Properties of HDL

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Product

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Recombinant Apolipoprotein A-I _Milano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks