Significance of ABCA1 in human carotid atherosclerotic plaques

Abstract

Abstract. The ATP-binding cassette transporter A1 (ABCA1) is an important effector in the regulation of cholesterol efflux from cells. In this study, we assessed the role of ABCA1 in human carotid atherosclerotic plaques (CAPs). We found that ABCA1 and retinoid X receptor α (RXRα) mRNAs were significantly increased in the atherosclerotic plaques compared to control arteries. The increased ABCA1 mRNA correlated with that of RXRα in plaques. According to the modified American Heart Association plaque classification, atherosclerotic specimens were assigned to three grades, and ABCA1 and RXRα mRNA levels were compared across plaques of different grades. Resultantly, plaques of grade Ⅱ and Ⅲ exhibited higher mRNA levels than grade Ⅰ, but there was no difference in mRNA levels between plaques of grade Ⅱ and Ⅲ. By contrast, ABCA1 and RXRα protein levels were notably reduced in plaques relative to control tissues. Similarly, plaques of grade Ⅱ and Ⅲ exhibited lower ABCA1 and RXRα protein levels than grade Ⅰ, and there was no difference in protein levels between plaques of grade Ⅱ and Ⅲ. Our findings suggest that decreased ABCA1 protein plays a key role in the pathogenesis of CAP; the regulation of ABCA1 may be mediated by RXRα and ABCA1 mRNA levels may serve as an indicator for plaque stability. IntroductionCarotid atherosclerotic plaque (CAP) is a predominant established risk factor for stroke, which is associated with high morbidity and mortality (1). Although the development of carotid plaques is influenced by environmental factors, such as elevated blood pressure and serum lipoprotein abnormalities (2), studies have been increasingly focusing on the genetic causes associated with the formation of atherosclerosis. ATP-binding cassette transporter 1 (ABCA1) has been recognized as a major mediator in the initial step of the reverse cholesterol transport, and was shown to facilitate the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins (apo)A-I and apoE from peripheral cells, resulting in the formation of nascent or pre-high-density lipoprotein (HDL) (3,4). Such a cholesterol efflux process prevents the accumulation of cholesterol or oxidative low-density lipoprotein (LDL) in peripheral cells, including macrophages within the arterial wall and, therefore, reduces the accumulation of atherosclerotic plaque.ABCA1 deficiency was indentified to be responsible for Tangier disease and familial HDL deficiency. These conditions are characterized by low levels of HDL, excessive deposition of cholesteryl esters in tissue macrophages and an increased risk for atherosclerotic disease (5). The underlying mechanism is thought to result from the failure of ABCA1 to transport cholesterol and phospholipids out of cells to form complexes with apolipoproteins to generate HDL (6). The intracellular sterol accumulation and subsequent development of foam cells may, as a result, lead to the atheromatous plaque. Due to its important role in atherosclerosis, increasing attention has been focused on ABCA1, so that therapeutic...

Cholesterol Efflux Capacity, Carotid Atherosclerosis, and Cerebrovascular Symptomatology

“…Liu et al 21 further noted that more advanced plaques (AHA plaque types III-VI) have lower ABCA1 protein expression compared with plaque types I and II, which are early lesions. Although our study contains only patients with advanced lesions, it is possible that fibroatheroma plaques express less ABCA1 than calcific or mainly fibrous plaques, whereas there is no difference in HDL, ApoAI, or C-reactive protein between patients with different AHA type V subtypes.…”

Expression pattern of the human ABC transporters in pluripotent embryonic stem cells and in their derivatives

“…One member of these multidrug transporters, ABCG2, has been shown to play a major role in the protection of stem cells against toxic compounds. In addition, the ABCB6 protein has been indicated to play a major role in the defense against toxic heme derivatives, while the ABCA1 protein has a key role in the extrusion of excess cellular lipid derivatives, especially cholesterol (see refs (4)(5)(6)(7)(8)(9) ).…”

Differences between the Molecular Mechanisms Underlying Ruptured and Non-Ruptured Carotid Plaques, and the Significance of ABCA1

“…Although several prior studies have compared ABCA1 levels between atherosclerotic plaques and healthy control tissues, our study demonstrates the significance of ABCA1 in carotid plaque rupture. For example, Albrecht et al [ 35 ] and Liu et al [ 36 ] reported that ABCA1 expression, which facilitates cholesterol efflux from cells, has different patterns at the mRNA and protein levels. The mRNA level of ABCA1 was higher, while its protein level was lower, in atherosclerotic plaques than in control tissues [ 35 , 36 ].…”

“…For example, Albrecht et al [ 35 ] and Liu et al [ 36 ] reported that ABCA1 expression, which facilitates cholesterol efflux from cells, has different patterns at the mRNA and protein levels. The mRNA level of ABCA1 was higher, while its protein level was lower, in atherosclerotic plaques than in control tissues [ 35 , 36 ]. Our results add to the existing evidence, demonstrating that ABCA1 level is different between ruptured and non-rupture plaques.…”