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High-Density Lipoprotein and Plaque Regression

1999; Lippincott Williams & Wilkins; Volume: 100; Issue: 17 Linguagem: Inglês

10.1161/01.cir.100.17.1762

1524-4539

Hayes M. Dansky, Edward A. Fisher,

Lipid metabolism and disorders

HomeCirculationVol. 100, No. 17High-Density Lipoprotein and Plaque Regression Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHigh-Density Lipoprotein and Plaque Regression The Good Cholesterol Gets Even Better Hayes M. Dansky and Edward A. Fisher Hayes M. DanskyHayes M. Dansky From the Laboratory of Biochemical Genetics and Metabolism (H.M.D.), The Rockefeller University, New York, NY, and Cardiovascular Institute (E.A.F.), Mount Sinai School of Medicine, New York, NY. and Edward A. FisherEdward A. Fisher From the Laboratory of Biochemical Genetics and Metabolism (H.M.D.), The Rockefeller University, New York, NY, and Cardiovascular Institute (E.A.F.), Mount Sinai School of Medicine, New York, NY. Originally published26 Oct 1999https://doi.org/10.1161/01.CIR.100.17.1762Circulation. 1999;100:1762–1763Primary and secondary prevention of coronary heart disease (CHD) has focused on lowering the LDL fraction of blood lipids not only because of the strong epidemiological evidence linking LDL to CHD, but also because pharmacological interventions have made it a highly modifiable risk factor. In contrast, although there is compelling epidemiological evidence that a low plasma level of HDL is also a powerful independent risk factor, it has received comparatively less attention as a therapeutic target. Contributing factors for this relative neglect undoubtedly include our poor understanding of the mechanisms by which low HDL increases cardiovascular risk and the fact that the most commonly used lipid-lowering drugs produce small increases in HDL levels.A variety of clinical and epidemiological studies have shown that apolipoprotein A-I (apoA-I), the major protein present on the surface of HDL particles, correlates with HDL cholesterol (HDL-C) levels, and like HDL, apoA-I correlates inversely with atherosclerosis susceptibility. Historically, experimental studies designed to directly investigate the antiatherogenic properties of apoA-I and HDL particles have been limited to in vitro models, given the limited ability to perform invasive studies in humans. The availability of transgenic and knockout mice and other animals has provided intact models of lipoprotein metabolism and atherosclerosis. Studies of such models have provided direct proof in mammals that an elevated plasma level of apoA-I results in increased HDL and in the inhibition of atherosclerotic lesion formation. For example, 2 independent studies12 demonstrated that transgenic expression of human apoA-I in hyperlipidemic apoE knockout mice resulted in a 2-fold increase in HDL-C and a dramatic inhibition of atherosclerotic lesion formation without changing non–HDL-C. Similar results have also been obtained in atherosclerosis-prone mice after HDL levels were raised by adenovirus-mediated expression of human apoA-I.3 Transgenic overexpression of apoA-I or weekly injection of purified apoA-I in cholesterol-fed rabbits also resulted in decreases in lesion formation.45 Although these studies demonstrate that apoA-I has a direct inhibitory effect on the initiation and progression of atherosclerotic lesions, they do not address what effects elevated HDL levels would have on established lesions. Because clinical and pathological studies have indicated that secondary and even primary prevention of CHD in humans most likely involves the stabilization or regression of existing coronary plaques, this question is of major clinical relevance.In the current issue of Circulation, Tangirala et al6 report for the first time that in addition to the aforementioned retardation of lesion initiation and progression, increased levels of apoA-I can indeed induce atherosclerotic lesion regression. The authors used the LDL receptor knockout mouse, a mouse model of familial hypercholesterolemia. After 5 weeks of consuming an atherogenic Western diet, mice were injected with either control virus or with recombinant defective adenovirus harboring the human apoA-I gene. This resulted in short-term (≈1 week) elevations in total apoA-I levels and a 50% increase in HDL-C. Whereas atherosclerosis progressed over the next 4 weeks in mice injected with the control virus, mice injected with the apoA-I recombinant adenovirus had 46% to 70% regression of atherosclerotic lesions. Regressed lesions "appeared less rich in foam cells and more fibrotic."6 Consistent with this was the quantitative analysis of immunocytochemical staining of lesions, which revealed a smaller percent area occupied by macrophages in mice that had received the apoA-I–containing adenovirus. These findings suggest that elevated levels of apoA-I and HDL-C can reduce the size and change the cellular composition of preexisting atherosclerotic lesions, at least those with complexity corresponding to American Heart Association types I and II (ie, fatty streaks).It is remarkable that significant lesion regression occurred after only 4 weeks, because peak expression of apoA-I and HDL-C levels lasted a relatively short time after injection of adenovirus. One possible explanation for the rapid regression is that the majority of lesions undergoing regression were macrophage foam-cell–containing fatty streaks, the type of lesions likely to be achieved in LDL-receptor knockout mice maintained on a Western diet for 9 weeks. If the lesions had contained more advanced characteristics, such as fibrous caps and necrotic cores, a rapid time course might not have been observed. Nonetheless, the demonstration of HDL-mediated regression of any type of lesion is a significant achievement, but readers are cautioned against concluding that regression of lesions is simply a reversal of progression. As the authors imply, the mechanisms and temporal nature of regression may be entirely distinct from the pathways involved in lesion progression.By what mechanisms did elevations in apoA-I and HDL-C induce regression in these studies? They are likely to be different from those involved in lowering LDL. For example, as the authors note, HDL particles contain potentially antiatherogenic components not found on LDL, such as apoA-IV, apoE, and paraoxonase, as well as lipid-processing enzymes such as LCAT (lecithin-cholesterol acyltransferase) and CETP (cholesteryl ester transfer protein). In addition to roles in cholesterol efflux, there are data implicating these proteins in metabolic, oxidative, or inflammatory processes affecting atherosclerosis.7 Although the mechanisms may differ, the findings by Tangirala et al6 are similar in some respects to what has been found in animal models in which regression is induced by LDL lowering. For example, in a recent study by Aikawa et al,8 LDL lowering induced by withdrawal of a high-cholesterol diet in rabbits with existing atherosclerotic lesions also resulted in regression with a decrease in macrophage number and an increase in the collagen content of the lesions. Relative decreases in macrophage number and increases in the fibrous content of lesions would be expected to result in clinical benefit, because human autopsy studies have demonstrated that the "vulnerable" plaques associated with acute coronary syndromes have increased numbers of macrophages, large lipid-rich necrotic cores, and thin fibrous caps.9Historically, significant atherosclerotic lesion regression in humans has been quite difficult to demonstrate. A multitude of "angiographic regression trials" have demonstrated that although LDL lowering results in a substantial reduction in coronary events, changes in lesion size based on serial quantitative angiographic measurements have been quite minimal. This has led to the hypothesis that LDL-lowering therapy stabilizes vulnerable atherosclerotic plaques without necessarily changing plaque size. Unfortunately, coronary angiography measurements are poor indices of lesion burden or characteristics, considering that pathological studies have demonstrated that atherosclerotic lesions can increase substantially in size through extensive outward growth and remodeling without affecting luminal diameter. Therefore, an exciting area of clinical research is the characterization of atherosclerotic lesions by the application of imaging modalities, notably intravascular ultrasound and MRI, to assess lesion features, such as size and composition. Although intravascular ultrasound imaging of coronary arteries is excellent for this purpose, it is an invasive technique and needs to be further developed to become a more routine clinical tool. MRI has the advantage of being noninvasive, but technical improvements are still needed before high-resolution images of coronary arteries are an everyday capability.In addition to providing insights into the relationship between HDL and lesion dynamics, the findings of Tangirala et al6 also support the goal to develop new therapeutic agents that induce long-lasting, large increases in apoA-I and HDL-C levels in humans. The desirability of this goal is also emphasized by the recently released Veterans Affairs HDL Intervention Trial,10 in which the modest raising of HDL-C by a fibric-acid derivative in patients with normal LDL levels resulted in a reduction in coronary events. An extremely attractive scenario for the future is the combination of imaging modalities (to allow the clinical evaluation of the effects on atherosclerotic lesions of agents that increase apoA-I and HDL-C levels) and model systems, such as the one presented by Tangirala et al, 6 with which to explore the mechanisms of actions of HDL and these agents. In this way, perhaps the "good" cholesterol can be made even "better."The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Edward A. Fisher, MD, PhD, Cardiovascular Institute, Mount Sinai School of Medicine, Box 1030, 1 Gustave Levy Place, New York, NY 10029. E-mail [email protected] References 1 Plump AS, Scott CJ, Breslow JL. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci U S A.1994; 91:9607–9611.CrossrefMedlineGoogle Scholar2 Paszty C, Maeda N, Verstuyft J, Rubin EM. Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. J Clin Invest.1994; 94:899–903.CrossrefMedlineGoogle Scholar3 Benoit P, Emmanuel F, Caillaud JM, Bassinet L, Castro G, Gallix P, Fruchart JC, Branellec D, Denefle P, Duverger N. Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models [see comments]. Circulation.1999; 99:105–110.CrossrefMedlineGoogle Scholar4 Duverger N, Kruth H, Emmanuel F, Caillaud JM, Viglietta C, Castro G, Tailleux A, Fievet C, Fruchart JC, Houdebine LM, Denefle P. Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits. Circulation.1996; 94:713–717.CrossrefMedlineGoogle Scholar5 Miyazaki A, Sakuma S, Morikawa W, Takiue T, Miake F, Terano T, Sakai M, Hakamata H, Sakamoto Y, Natio M, Ruan Y, Takahashi K, Ohta T, Horiuchi S. Intravenous injection of rabbit apolipoprotein A-I inhibits the progression of atherosclerosis in cholesterol-fed rabbits. Arterioscler Thromb Vasc Biol.1995; 15:1882–1888.CrossrefMedlineGoogle Scholar6 Tangirala RK, Tsukamoto K, Chun SH, Usher D, Puré E, Rader DJ. Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. Circulation.1999; 100:1816–1822.CrossrefMedlineGoogle Scholar7 van Vlijmen BJ, Herz J. Gene targets and approaches for raising HDL. Circulation.1999; 99:12–14. Editorial.LinkGoogle Scholar8 Aikawa M, Rabkin E, Okada Y, Voglic SJ, Clinton SK, Brinckerhoff CE, Sukhova GK, Libby P. Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization [see comments]. Circulation.1998; 97:2433–2444.CrossrefMedlineGoogle Scholar9 Libby P. Molecular bases of the acute coronary syndromes. Circulation.1995; 91:2844–2850.CrossrefMedlineGoogle Scholar10 Rubins H, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. 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Moore K and Nagle D (2000) COMPLEX TRAIT ANALYSIS IN THE MOUSE: The Strengths, The Limitations and The Promise Yet To Come, Annual Review of Genetics, 10.1146/annurev.genet.34.1.653, 34:1, (653-686), Online publication date: 1-Dec-2000. October 26, 1999Vol 100, Issue 17 Advertisement Article InformationMetrics Copyright © 1999 by American Heart Associationhttps://doi.org/10.1161/01.CIR.100.17.1762 Originally publishedOctober 26, 1999 KeywordscholesterollipoproteinsatherosclerosisEditorialsPDF download Advertisement