Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiovascular calcification is a common consequence of diabetes. High fat diets induce diabetes and arterial calcification in male low density lipoprotein receptor (LDLR) -/- mice; calcification occurs via Msx2 signaling that promotes the osteogenic differentiation of arterial myofibroblasts. We studied regulation of arterial osteogenesis by human parathyroid hormone (PTH) (1-34) (also called teriparatide) in LDLR -/- mice fed diabetogenic diets for 4 weeks. LDLR -/- mice were treated with vehicle or 0.4 mg/kg of PTH(1-34) subcutaneously five times/week. Gene expression was determined from single aortas and hind limb RNA by fluorescence reverse transcription-PCR. Valve calcification was determined by histological staining of cardiac sections using image analysis to quantify valve leaflet mineralization. PTH(1-34) increased bone mineral content (by dual energy x-ray absorptiometry) in LDLR -/- mice, with induction of osseous osteopontin (OPN) expression and serum OPN levels (>150 nM); PTH(1-34) did not significantly change serum glucose, lipids, body weight, or fat mass. PTH(1-34) suppressed aortic OPN and Msx2 expression >50% and decreased cardiac valve calcification 80% (8.3 +/- 1.5% versus 1.4 +/- 0.5%; p < 0.001). Of the known circulating regulators of vascular calcification (OPN, osteoprotegerin, and leptin), PTH(1-34) regulated only serum OPN. We therefore studied actions of PTH(1-34) and OPN in vitro on cells induced to mineralize with Msx2. OPN (5-50 nM) reversed Msx2-induced mineralization. PTH(1-34) inhibited mineralization by 40% and down-regulated Msx2 in aortic myofibroblasts. PTH(1-34) inhibits vascular calcification and aortic osteogenic differentiation via direct actions and potentially via circulating OPN. PTH(1-34) exerts beneficial actions at early stages of macrovascular disease responses to diabetes and dyslipidemia.
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PMID:Teriparatide (human parathyroid hormone (1-34)) inhibits osteogenic vascular calcification in diabetic low density lipoprotein receptor-deficient mice. 1450 75

Vascular calcification increasingly afflicts our aging and dysmetabolic population, predisposing patients to cardiovascular mortality and lower extremity amputation. Active osteogenic processes are evident in most histoanatomic variants, including elaboration of BMP2-Msx2 signals required for craniofacial bone formation. We developed an animal model of diet-induced diabetes, dyslipidemia, and vascular calcification. High-fat diets promote vascular calcification in male low-density lipoprotein receptor (LDLR)-deficient mice, with concomitant upregulation of aortic BMP2 and Msx2 gene expression. We wished to test if Msx2 exerts pro-calcific actions during vascular calcification, as it does in craniofacial bone. We studied CMV-Msx2Tg+;LDLR+ transgenic mice (C57Bl/6), a model previously demonstrated to recapitulate features of Msx2 signaling during craniosynostosis. After 16 weeks of fatty diets, vascular calcification was studied in CMV-Msx2Tg+ versus nontransgenic sibs. Only CMV-Msx2Tg+ mice fed high-fat diets exhibited vascular calcium accumulation by alizarin red staining, noted in the tunica media of coronary arteries and the aorta. Gene expression studies revealed that while Msx2 was expressed primarily in adventitial cells, alkaline phosphatase (ALP) expression and calcification occurred primarily in the tunica media. Msx2 promotes the elaboration of a pro-osteogenic milieu by upregulating expression of Wingless type (Wnt) ligands while downregulating the canonical antagonist, Dickkopf (Dkk1). Msx2 upregulates aortic Wnt signaling in vivo, revealed by the analysis of TOPGAL+ (Wnt reporter) versus CMV-Msx2Tg+; TOPGAL+ mice. Aortic Msx2 exerts pro-osteogenic signaling in vivo and in vitro, mediated in part via the enhancement of paracrine Wnt signaling. Strategies that selectively inhibit aortic Msx2-Wnt cascades may help diminish the initiation and progression of diabetic vascular disease.
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PMID:Osteogenic regulation of vascular calcification. 1683 33

Extrarenal calcifications, particularly affecting the cardiovascular system, are common observations which can be a source of serious complications in patients with chronic renal disease, especially those on dialysis. In these patients, cardiovascular disease - myocardial infarction, arrhythmia, calcified valvulopathy, stroke, peripheral ischemic arteriopathy, calciphylaxy, etc. - is the leading cause of death (more than 50%). These complications are closely related to the presence of vascular calcifications (VC) which are much more frequent, severe, and progressive than in the general population. Previously, these calcifications were considered to arise via a passive process within the context of comorbid conditions without specific signs of gravity: high blood pressure, atherosclerosis, aging, diabetes, smoking, dyslipidemia, chronic micro-inflammation, hyperhomocysteinemia, disorders of calcium-phosphorus metabolism. It is now established that VC arise via a complex, probably regulated, active process analogous to the processes leading to bone formation and/or remodeling. New insight provided by a large body of work designed to ascertain the mechanisms underlying the onset of VC has enabled the development of new diagnostic and therapeutic approaches. It is now possible to identify factors clearly favoring the formation of VC: TNF-alpha (which stimulates cell necrosis/apoptosis), CRP, oxidized lipids, AGEs, leptin, inorganic phosphate, high calcium-phosphorus product (CaxPO(4)), calcium, 1,25-OH(2)D(3) and Vitamin D(3), PTHrP (via an intracrine pathway), cyclic AMP, TGF-beta, bone morphogenic protein 2 (BMP2) and factors protective against the formation of VC: magnesium, HDL, inorganic pyrophosphate, albumin, ahsg/fetuin A, osteopontin (OPN), osteoprotegerin (OPG), osteonectin (ON), bone morphogenic protein 7 (BMP7), klotho, PTHrP (via a paracrine pathway), matrix gla protein (MGP), PTH (via Msx2) and vitamin K. In conclusion, until recently, neglected disorders of calcium-phosphorus metabolism are currently recognized as the main actors in the process leading to vascular mediacalcosis in patients with chronic kidney failure.
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PMID:[Origin of the mediacalcosis in kidney failure]. 1934 26