[Molecular diagnosis and combined lipid lowering therapy of heterozygous familial hypercholesterolemia. Report of one case]. / Hipercolesterolemia familiar heterocigota: diagnóstico molecular y terapia combinada. Caso clínico.

Heterozygous familial hypercholesterolemia affects one every 400 individuals, is caused by mutations in the LDL receptor gene and is associated with premature coronary artery disease. Nowadays, LDL cholesterol can be efficiently reduced with the new therapies to reduce blood lipids. We report a female patient who consulted in 1975, when she was 46 years old, for severe hypercholesterolemia. In 2003, a sample of leukocyte DNA was obtained and the uncommon 1705+1G>A mutation of the LDL receptor gene was detected. No mutations in the apolipoprotein B gene were found. The patient was treated successfully with simvastatin 80 mg/day and ezetimibe 10 mg/day and LDL cholesterol levels were reduced below 200 mg/dl.

Hipercolesterolemia familiar heterocigota: diagnóstico molecular y terapia combinada. Caso clínico / Molecular diagnosis and combined lipid lowering therapy of heterozygous familial hypercholesterolemia: Report of one case

Heterozygous familial hypercholesterolemia affects one every 400 individuals, is caused by mutations in the LDL receptor gene and is associated with premature coronary artery disease. Nowadays, LDL cholesterol can be efficiently reduced with the new therapies to reduce blood lipids. We report a female patient who consulted in 1975, when she was 46 years old, for severe hypercholesterolemia. In 2003, a sample of leukocyte DNA was obtained and the uncommon 1705 + 1G >A mutation of the LDL receptor gene was detected. No mutations in the apolipoprotein B gene were found. The patient was treated successfully with simvastatin 80 mg/day and ezetimibe 10 mg/day and LDL cholesterol levels were reduced below 200 mg/dl.

Triglyceride-rich lipoproteins prime aortic endothelium for an enhanced inflammatory response to tumor necrosis factor-alpha.

High levels of triglyceride-rich lipoproteins (TGRLs) in blood are linked to development of atherosclerosis, yet the mechanisms by which these particles initiate inflammation of endothelium are unknown. TGRL isolated from human plasma during the postprandial state was examined for its capacity to bind to cultured human aortic endothelial cells (HAECs) and alter the acute inflammatory response to tumor necrosis factor-alpha. HAECs were repetitively incubated with dietary levels of freshly isolated TGRL for 2 hours per day for 1 to 3 days to mimic postprandial lipidemia. TGRL induced membrane upregulation of the low-density lipoprotein family receptors LRP and LR11, which was inhibited by the low-density lipoprotein receptor-associated protein-1. TGRLs alone did not elicit inflammation in HAECs but enhanced the inflammatory response via a 10-fold increase in sensitivity to cytokine stimulation. This was reflected by increased mitogen-activated protein kinase activation, nuclear translocation of NF-kappaB, amplified expression of endothelial selectin and VCAM-1, and a subsequent increase in monocyte-specific recruitment under shear flow as quantified in a microfabricated vascular mimetic device.

Wnt signaling regulates the invasion capacity of human mesenchymal stem cells.

Human mesenchymal stem cells (hMSCs) exhibit the potential to contribute to a wide variety of endogenous organ tissue repair. However, the signals governing hMSC mobilization out of the bone marrow, release into the bloodstream, and migration/invasion into the target tissue are largely unknown. Since canonical Wnt signaling regulates not only tumor but also various stem cell attributes, we hypothesized that this signal transduction pathway might also be involved in governing the transmigration of hMSCs through human extracellular matrix (ECM). Stimulation of hMSCs with recombinant Wnt3a or LiCl resulted in the accumulation of the transcriptional activator beta-catenin, its translocation into the nucleus, and the upregulation of typical Wnt target genes such as cyclin D1 and membrane-type matrix metalloproteinase-1 (MT1-MMP). Moreover, both stimuli significantly enhanced hMSC proliferation up to 40%. In addition, an increase of more than twofold in the ability of hMSCs to transmigrate through Transwell filters coated with human ECM was observed. In a reverse approach, Wnt signaling in hMSCs was inhibited by knocking down the expression of either beta-catenin or low-density lipoprotein receptor-related protein 5 using RNA interference technology. These inhibition strategies resulted in downregulation of the Wnt target genes cyclin D1 and MT1-MMP, in a reduced proliferation rate, and in a strikingly diminished invasion capacity (64% and 52%). Taken together, this study provides for the first time decisive evidence that canonical Wnt signaling is critically involved in the regulation of the proliferation, as well as of the migration/invasion capacity of hMSCs, representing essential stem cell features indispensable during tissue regeneration processes.

Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway.

BACKGROUND: Calcific aortic valve disease is the most common indication for surgical valve replacement in the United States. The cellular mechanisms of valve calcification are not well understood. We have previously shown that cellular proliferation and osteoblastogenesis are important in the development of valvular heart disease. Lrp5, a known low-density receptor-related protein, plays an essential role in cellular proliferation and osteoblastogenesis via the beta-catenin signaling pathway. We hypothesize that Lrp5 also plays a role in aortic valve (AV) calcification in experimental hypercholesterolemia. METHODS AND RESULTS: We examined the effects of cholesterol and atorvastatin in Watanabe rabbits (n=54). Group I (n=18) received a normal diet, group II (n=18) a 0.25% cholesterol diet, and group III (n=18) a 0.25% (w/w) cholesterol diet with atorvastatin for the development of calcification. The AVs were examined for cellular proliferation, Lrp5/beta-catenin, and bone matrix markers. Bone formation was assessed by micro-computed tomography, calcein injection, and osteopontin expression. Low-density lipoprotein with and without atorvastatin was also tested in AV myofibroblasts for cellular proliferation and regulation of the Lrp5/beta-catenin pathway. Our results demonstrate that the cholesterol diet induced complex bone formations in the calcified AVs with an increase in the Lrp5 receptors, osteopontin, and p42/44 expression. Atorvastatin reduced bone formation, cellular proliferation, and Lrp5/beta-catenin protein levels in the AVs. In vitro analysis confirmed the Lrp5/beta-catenin expression in myofibroblast cell proliferation. CONCLUSIONS: Hypercholesterolemic AV calcification is attenuated by atorvastatin and is mediated in part by the Lrp5/beta-catenin pathway. This developmental pathway may be important in the signaling pathway of this disease.