Spontaneous atherosclerosis in the proximal aorta of LPA transgenic mice on a normal diet

Berg, Kåre; Svindland, Aud; Smith, A. J.; Lawn, Richard M.; Djurovic, Srdjan; Alestrøm, A.; Aleström, Peter; Eliassen, Knut Arnet

doi:10.1016/s0021-9150(01)00772-9

Cited by 23 publications

(22 citation statements)

References 21 publications

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“…22 Over such genetic backgrounds, the role of numerous genes in atherogenesis have been assessed by transgenic addition or knockout subtraction. 23 It is worth noting that transgenic expression of apo(a) alone also resulted in significant aortic lesions in mice maintained on a low-fat diet for 66 weeks, 24 providing direct evidence for a causal relationship between apo(a) and atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous Atherosclerosis in Aged Lipoprotein Lipase–Deficient Mice With Severe Hypertriglyceridemia on a Normal Chow Diet

Zhang

Xian

et al. 2008

Circulation Research

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Abstract-Large-scale epidemiological studies have revealed a strong association between hypertriglyceridemia and coronary arteriosclerotic disease. However, there are conflicting reports whether the severe hypertriglyceridemia caused by lipoprotein lipase (LPL) deficiency is pro-or antiatherogenic. To determine the effect of LPL deficiency on atherosclerosis, we pursued long-term observation of the development of atherosclerotic lesions in an LPL gene deficient mouse model. At 4 months of age, homozygous LPL-deficient mice exhibited severe hypertriglyceridemia but no signs of aortic atherosclerotic lesions. At Ͼ15 months of age, these mice developed foam cell-rich atherosclerotic lesions at the aortic root, whereas wild-type and heterozygous mice were lesion-free at the same age. Further investigation revealed that plasma malondialdehyde levels in Ͼ15-month-old LPL-deficient mice were significantly higher than those of heterozygous and wild-type mice. Electron spin resonance analysis showed a marked increase in oxidative susceptibility of chylomicrons from the aged LPL-deficient mice.

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Section: Discussionmentioning

confidence: 99%

Spontaneous Atherosclerosis in Aged Lipoprotein Lipase–Deficient Mice With Severe Hypertriglyceridemia on a Normal Chow Diet

Zhang

Xian

et al. 2008

Circulation Research

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“…For instance, we have learned that transgenic mice expressing human apo(a) develop early atherosclerotic lesions when fed either a high-fat diet [43] or a normal diet in adult mice [44]. As already mentioned, in the transgenic mouse model, the apo(a)-induced lesions were significantly less expressed when the Arg72 Lys -mutant replaced the wild-type Trp72 phenotype [20].…”

Section: Lessons From Animal Modelsmentioning

confidence: 95%

Lipoprotein(a) and the atherothrombotic process: Mechanistic insights and clinical implications

Scanu

2003

Curr Atheroscler Rep

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Although many epidemiologic studies have pointed at an association between plasma levels of lipoprotein(a) (Lp(a)) and cardiovascular risk, the data obtained have been conflicting because of a number of factors, particularly those dealing with plasma storage, lack of assay standardization, population sample size, age, gender, ethnic variations, and variable disease endpoints. Moreover, the attention has been primarily focused on whole Lp(a), with relatively less emphasis on its constituent apolipoprotein(a) and on the apolipoprotein B100-containing lipoprotein, mainly low-density lipoprotein (LDL), to which apolipoprotein(a) is linked. According to recent studies, small-size apolipoprotein(a) isoforms may represent a cardiovascular risk factor either by themselves or synergistically with plasma Lp(a) concentration. Moreover, the density properties of the LDL moiety may have an impact on Lp(a) pathogenicity. It has also become apparent that Lp(a) can be modified by oxidative events and by the action of lipolytic and proteolytic enzymes with the generation of products that exhibit atherothrombogenic potential. The role of the O-glycans linked to the inter-kringle linkers of apolipoprotein(a) is also emerging. This information is raising the awareness of the pleiotropic functions of Lp(a) and is opening new vistas on pathogenetic mechanisms whose knowledge is essential for developing rational therapies against this complex cardiovascular pathogen.

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“…To address this void, transgenic animal models have been created using mice and rabbits. [91][92][93][94][95][96] Initial attempts to generate a transgenic model for Lp(a) relied on the formation of this particle from human apo(a) and murine apoB. Although murine apoB did not form an Lp(a) complex with human apo(a), important insights into predictors of Lp(a) formation were gained from these studies.…”

Section: Cardiovascular Risk Properties: Animal Models and In Vitro Smentioning

confidence: 99%

“…94 Studies in rabbits transgenic for Lp(a) have also provided support for a pro-atherogenic role. 95,96 In addition, studies in transgenic mice as well as from an arterial injury model in cynomolgus monkeys have provided support for a prothrombotic and/or antifibrinolytic role of Lp(a).…”

Section: Berglund and Ramakrishnan Lipoprotein (A): An Elusive Cardiomentioning

confidence: 99%

Lipoprotein(a)

Berglund

Ramakrishnan

2004

ATVB

199

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Abstract-Lipoprotein (a) [Lp(a)], is present only in humans, Old World nonhuman primates, and the European hedgehog.Lp(a) has many properties in common with low-density lipoprotein (LDL) but contains a unique protein, apo(a), which is structurally different from other apolipoproteins. The size of the apo(a) gene is highly variable, resulting in the protein molecular weight ranging from 300 to 800 kDa; this large variation may be caused by neutral evolution in the absence of any selection advantage. Apo(a) influences to a major extent metabolic and physicochemical properties of Lp(a), and the size polymorphism of the apo(a) gene contributes to the pronounced heterogeneity of Lp(a). There is an inverse relationship between apo(a) size and Lp(a) levels; however, this pattern is complex. For a given apo(a) size, there is a considerable variation in Lp(a) levels across individuals, underscoring the importance to assess allele-specific Lp(a) levels. Further, Lp(a) levels differ between populations, and blacks have generally higher levels than Asians and whites, adjusting for apo(a) sizes. In addition to the apo(a) size polymorphism, an upstream pentanucleotide repeat (TTTTA n ) affects Lp(a) levels. Several meta-analyses have provided support for an association between Lp(a) and coronary artery disease, and the levels of Lp(a) carried in particles with smaller size apo(a) isoforms are associated with cardiovascular disease or with preclinical vascular changes. Further, there is an interaction between Lp(a) and other risk factors for cardiovascular disease. The physiological role of Lp(a) is unknown, although a majority of studies implicate Lp(a) as a risk factor. Key Words: atherosclerosis Ⅲ genetics Ⅲ blacks Ⅲ lipids L ipoprotein(a) [Lp(a)] was first described Ϸ40 years ago, and interest in this entity is largely derived from its putative role as a cardiovascular risk factor. 1-3 Underlying this concept is the realization that Lp(a) has many properties in common with low-density lipoprotein (LDL), a wellestablished atherogenic factor for coronary artery disease. [2][3][4][5] Thus, the composition of the lipid moiety of Lp(a), including its cholesteryl ester-rich core, is similar to that of LDL, and the density distribution of the lipid moiety of Lp(a) in a given subject closely mirrors that of LDL. 6 Furthermore, like LDL, each particle of Lp(a) has 1 molecule of apolipoprotein B-100 (apo B-100); both apolipoprotein B (apoB) and the lipid core are pro-atherogenic. 7 Also, Lp(a) clearance rates are similar to those for LDL. 8,9 However, Lp(a) contains a unique protein, apolipoprotein(a) [apo(a)], which is structurally different from other apolipoproteins, having a hydrophilic, carbohydrate-rich structure with no amphipathic helices. 5,10,11 Apo(a) is linked to apoB through a single disulfide bond connecting their C-terminal regions [12][13][14][15] (Figure 1).The presence of apo(a) influences to a major extent metabolic and physicochemical properties of Lp(a). 16 -18 Notably, the cysteine residue in apoB involved in ...

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Spontaneous atherosclerosis in the proximal aorta of LPA transgenic mice on a normal diet

Cited by 23 publications

References 21 publications

Spontaneous Atherosclerosis in Aged Lipoprotein Lipase–Deficient Mice With Severe Hypertriglyceridemia on a Normal Chow Diet

Spontaneous Atherosclerosis in Aged Lipoprotein Lipase–Deficient Mice With Severe Hypertriglyceridemia on a Normal Chow Diet

Lipoprotein(a) and the atherothrombotic process: Mechanistic insights and clinical implications

Lipoprotein(a)

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