Apo E is a 34-kDa plasma protein important for the metabolism of plasma lipoproteins (1). Like other apolipoproteins, apo E contains multiple 22-amino acid repeats that form amphipathic helices, enabling it to associate with the surface of plasma lipoproteins. Apo E also contains a stretch of basic residues (136-150) that is important for high-affinity binding to the LDL receptor and subsequent endocytosis of the associated lipoprotein particle (2). In addition, apo E mediates lipoprotein interactions with LDL receptor-related protein (LRP) (3), the VLDL receptor (4), other lipoprotein receptors (5), endothelial heparin sulfate (6), and plasma lipases (7,8). The phenotype of severe hyperlipidemia and spontaneous development of atherosclerosis in mice lacking apo E clearly demonstrates the central role of apo E in mammalian lipid metabolism (9, 10).In humans, the APOE gene is polymorphic and has 3 alleles: APOE*2, APOE*3, and APOE*4. These alleles have frequencies of 7%, 77%, and 15%, respectively, in the general population (11). The APOE*3 allele codes for cysteine at position 112 and for arginine at 158. The APOE*2 allele codes cysteines at both positions, whereas the APOE*4 allele codes for arginines at both positions. Various population-based studies have suggested that the different APOE alleles have distinct influences on lipid metabolism in humans. Possession of at least 1 copy of the APOE*2 allele has been associated with higher plasma apo E (12) and lower plasma cholesterol, LDL cholesterol, and apo B levels (11) when compared with APOE*3 homozygotes. The APOE*2 allele is also associated with lower risk of coronary artery disease (13), except in 5-10% of APOE*2 homozygotes who develop type III hyperlipoproteinemia and premature atherosclerosis (14). On the other hand, the presence of at least 1 APOE*4 allele is associated with lower plasma apo E (12) and increased plasma cholesterol, LDL cholesterol, and apo B levels (11), and a greater risk of coronary artery disease (13), when compared with APOE*3 homozygotes. Davignon et al. (11) estimate that the apo E polymorphism accounts for 2.8% of the variation of risk for atherosclerosis, which is a large contribution for a single locus in this complex, polygenic disease.The availability of a well-defined model system should benefit studies of the role of the human apo E polymorphism in lipid metabolism and atherosclerosis. To develop such a model, we have used gene targeting to replace the murine Apoe gene with the 3 human APOE alleles. These mice retain the murine Apoe regulatory sequences and solely produce human apo E proteins with different We have generated mice expressing the human apo E4 isoform in place of the endogenous murine apo E protein and have compared them with mice expressing the human apo E3 isoform. Plasma lipid and apolipoprotein levels in the mice expressing only the apo E4 isoform (4/4) did not differ significantly from those in mice with the apo E3 isoform (3/3) on chow and were equally elevated in response to increased lipid and choles...

Platelet-derived growth factor (PDGF) is a mitogen and chemoattractant for vascular smooth muscle cells (VSMCs). However, the direct effects of PDGF receptor β (PDGFRβ) activation on VSMCs have not been studied in the context of atherosclerosis. Here, we present a new mouse model of atherosclerosis with an activating mutation in PDGFRβ. Increased PDGFRβ signaling induces chemokine secretion and leads to leukocyte accumulation in the adventitia and media of the aorta. Furthermore, PDGFRβD849V amplifies and accelerates atherosclerosis in hypercholesterolemic ApoE−/− or Ldlr−/− mice. Intriguingly, increased PDGFRβ signaling promotes advanced plaque formation at novel sites in the thoracic aorta and coronary arteries. However, deletion of the PDGFRβ-activated transcription factor STAT1 in VSMCs alleviates inflammation of the arterial wall and reduces plaque burden. These results demonstrate that PDGFRβ pathway activation has a profound effect on vascular disease and support the conclusion that inflammation in the outer arterial layers is a driving process for atherosclerosis.

Heparan and chondroitin/dermatan sulfated proteoglycans have a wide range of roles in cellular and tissue homeostasis including growth factor function, morphogen gradient formation, and co-receptor activity. Proteoglycan assembly initiates with a xylose monosaccharide covalently attached by either xylosyltransferase I or II. Three individuals from two families were found that exhibited similar phenotypes. The index case subjects were two brothers, individuals 1 and 2, who presented with osteoporosis, cataracts, sensorineural hearing loss, and mild learning defects. Whole exome sequence analyses showed that both individuals had a homozygous c.692dup mutation (GenBank: NM_022167.3) in the xylosyltransferase II locus (XYLT2) (MIM: 608125), causing reduced XYLT2 mRNA and low circulating xylosyltransferase (XylT) activity. In an unrelated boy (individual 3) from the second family, we noted low serum XylT activity. Sanger sequencing of XYLT2 in this individual revealed a c.520del mutation in exon 2 that resulted in a frameshift and premature stop codon (p.Ala174Profs*35). Fibroblasts from individuals 1 and 2 showed a range of defects including reduced XylT activity, GAG incorporation of 35 SO 4 , and heparan sulfate proteoglycan assembly. These studies demonstrate that human XylT2 deficiency results in vertebral compression fractures, sensorineural hearing loss, eye defects, and heart defects, a phenotype that is similar to the autosomal-recessive disorder spondylo-ocular syndrome of unknown cause. This phenotype is different from what has been reported in individuals with other linker enzyme deficiencies. These studies illustrate that the cells of the lens, retina, heart muscle, inner ear, and bone are dependent on XylT2 for proteoglycan assembly in humans.Proteoglycans (PGs) are a class of surface-associated and extracellular matrix proteins that play a key role in many tissues.