Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases (MMPs) are members of an enzyme family that require a zinc ion in their active site for catalytic activity. MMPs are critical for maintaining tissue allostasis. MMPs are active at neutral pH and can therefore catalyze the normal turnover of extracellular matrix (ECM) macromolecules such as the interstitial and basement membrane collagens, proteoglycans such as aggrecan, decorin, biglycan, fibromodulin and versican as well as accessory ECM proteins such as fibronectin. Members of the MMP family include the "classical" MMPs, the membrane-bound MMPs (MT-MMPs) the ADAMs (a disintegrin and metalloproteinase; adamlysins) and the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif). There are more than 20 members in the MMP and ADAMTS family including the collagenases, gelatinases, stromelysins, some elastases and aggrecanases. Adamlysins are membrane-bound MMPs that also degrade aggrecan, but more importantly, one ADAM family member (i.e.ADAM-17) is a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE) that activates pro-TNF-alpha. Most of the MMPs are synthesized as inactive latent enzymes. Conversion to the active enzyme is generally mediated by activator systems that include plasminogen activator or the pro-hormone convertase, furin. MMP activity is regulated by a group of endogenous proteins, called, tissue inhibitor of metalloproteinases (TIMPs) that bind to active and alternative sites of the activated MMP. Significant advances have occurred in the understanding of the regulation of MMPs, ADAMs and ADAMTSs gene expression. In addition, development of MMP inhibitors to study MMP structure/function relationships spawned many studies to determine the effectiveness of MMP inhibitors in regulating abnormal connective tissue turnover. In addition, development of MMP null mice carrying specific MMP deletions has provided an opportunity to explore the role of MMPs in normal development as well as in such diverse conditions and diseases as skeletal dysplasias, coronary artery and heart disease, arthritis, cancer, and brain disorders.
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PMID:Matrix metalloproteinases (MMPs) in health and disease: an overview. 1636 48

The cardiac extracellular matrix (ECM) is a complex architectural network consisting of structural and nonstructural proteins, creating strength and plasticity. The nonstructural compartment of the ECM houses a variety of proteins, which are vital for ECM plasticity, and can be divided into 3 major groups: glycoproteins, proteoglycans, and glycosaminoglycans. The common denominator for these groups is glycosylation, which refers to the decoration of proteins or lipids with sugars. This review will discuss the fundamental role of the matrix in cardiac development, homeostasis, and remodeling, from a glycobiology point of view. Glycoproteins (eg, thrombospondins, secreted protein acidic and rich in cysteine, tenascins), proteoglycans (eg, versican, syndecans, biglycan), and glycosaminoglycans (eg, hyaluronan, heparan sulfate) are upregulated on cardiac injury and regulate key processes in the remodeling myocardium such as inflammation, fibrosis, and angiogenesis. Albeit some parallels can be made regarding the processes these proteins are involved in, their specific functions are extremely diverse. In fact, under varying conditions, individual proteins can even have opposing functions, making spatiotemporal contribution of these proteins in the rearrangement of multifaceted ECM very hard to grasp. Alterations of protein characteristics by the addition of sugars may explain the immense, yet tightly regulated, variability of the remodeling cardiac matrix. Understanding the role of glycosylation in altering the ultimate function of glycoproteins, proteoglycans, and glycosaminoglycans in the myocardium may lead to the development of new biochemical structures or compounds with great therapeutic potential for patients with heart disease.
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PMID:Myocardial extracellular matrix: an ever-changing and diverse entity. 2457 67

The fundamental importance of the proteoglycan versican to early heart formation was clearly demonstrated by the Vcan null mouse called heart defect (hdf). Total absence of the Vcan gene halts heart development at a stage prior to the heart's pulmonary/aortic outlet segment growth. This creates a problem for determining the significance of versican's expression in the forming valve precursors and vascular wall of the pulmonary and aortic roots. This study presents data from a mouse model, Vcan ((tm1Zim)), of heart defects that results from deletion of exon 7 in the Vcan gene. Loss of exon 7 prevents expression of two of the four alternative splice forms of the Vcan gene. Mice homozygous for the exon 7 deletion survive into adulthood, however, the inability to express the V2 or V0 forms of versican results in ventricular septal defects, smaller cushions/valve leaflets with diminished myocardialization and altered pulmonary and aortic outflow tracts. We correlate these phenotypic findings with a large-scale differential protein expression profiling to identify compensatory alterations in cardiac protein expression at E13.5 post coitus that result from the absence of Vcan exon 7. The Vcan ((tm1Zim)) hearts show significant changes in the relative abundance of several cytoskeletal and muscle contraction proteins including some previously associated with heart disease. These alterations define a protein fingerprint that provides insight to the observed deficiencies in pre-valvular/septal cushion mesenchyme and the stability of the myocardial phenotype required for alignment of the outflow tract with the heart ventricles.
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PMID:Imbalanced expression of Vcan mRNA splice form proteins alters heart morphology and cellular protein profiles. 2458 47

Congenital heart valve defects in humans occur in approximately 2% of live births and are a major source of compromised cardiac function. In this study we demonstrate that normal heart valve development and cardiac function are dependent upon Galnt1, the gene that encodes a member of the family of glycosyltransferases (GalNAc-Ts) responsible for the initiation of mucin-type O-glycosylation. In the adult mouse, compromised cardiac function that mimics human congenital heart disease, including aortic and pulmonary valve stenosis and regurgitation; altered ejection fraction; and cardiac dilation, was observed in Galnt1 null animals. The underlying phenotype is aberrant valve formation caused by increased cell proliferation within the outflow tract cushion of developing hearts, which is first detected at developmental stage E11.5. Developing valves from Galnt1 deficient animals displayed reduced levels of the proteases ADAMTS1 and ADAMTS5, decreased cleavage of the proteoglycan versican and increased levels of other extracellular matrix proteins. We also observed increased BMP and MAPK signaling. Taken together, the ablation of Galnt1 appears to disrupt the formation/remodeling of the extracellular matrix and alters conserved signaling pathways that regulate cell proliferation. Our study provides insight into the role of this conserved protein modification in cardiac valve development and may represent a new model for idiopathic valve disease.
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PMID:Galnt1 is required for normal heart valve development and cardiac function. 2561 42

Pulmonary arterial hypertension (PAH) is a lethal condition for which there is no effective curative pharmacotherapy. PAH is characterized by vasoconstriction, wall thickening of pulmonary arteries, and increased vascular resistance. Versican is a chondroitin sulfate proteoglycan in the vascular extracellular matrix that accumulates following vascular injury and promotes smooth-muscle cell proliferation in systemic arteries. Here, we investigated whether versican may play a similar role in PAH. Paraffin-embedded lung sections from patients who underwent lung transplantation to treat PAH were used for immunohistochemistry. The etiologies of PAH in the subjects involved in this study were idiopathic PAH, scleroderma, and congenital heart disease (atrial septal defect) with left-to-right shunt. Independent of the underlying etiology, increased versican immunostaining was observed in areas of medial thickening, in neointima, and in plexiform lesions. Western blot of lung tissue lysates confirmed accumulation of versican in patients with PAH. Double staining for versican and CD45 showed only occasional colocalization in neointima of high-grade lesions and plexiform lesions. In vitro, metabolic labeling with [(35)S]sulfate showed that human pulmonary artery smooth-muscle cells (hPASMCs) produce mainly chondroitin sulfate glycosaminoglycans. In addition, hypoxia, but not cyclic stretch, was demonstrated to increase both versican messenger RNA expression and protein synthesis by hPASMCs. Versican accumulates in vascular lesions of PAH, and the amount of versican correlates more with lesion severity than with underlying etiology or inflammation. Hypoxia is a possible regulator of versican accumulation, which may promote proliferation of pulmonary smooth-muscle cells and vascular remodeling in PAH.
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PMID:Versican accumulates in vascular lesions in pulmonary arterial hypertension. 2768 12