Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0264733 (ventricular dilatation)
 2,163 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following myocardial infarction, extracellular matrix (ECM) is disrupted, which leads to the generation of collagen- and elastin-derived peptides (CDPs and EDPs, respectively). To investigate whether ECM-derived peptides (i.e., CDPs and EDPs) induce extracellular proteinases in human heart fibroblast (HHF) cells, we isolated CDP and EDP using gelfiltration and antibody affinity column chromatography. The CDP and EDP were characterized by their intrinsic fluorescence due to crosslink structure (pyridinoline and desmosine, respectively) and by immunoblot analysis using anti-desmosine antibody. Neutrophil elastase and cathepsin G were identified using selective chromogenic substrates and by their specific inhibition with alpha1-proteinase inhibitor and alpha1-antichymotrypsin, respectively. Elastase and cathepsin G were elevated in the infarcted tissue. Selective inhibition of matrix metalloproteinase (MMP) by a higher concentration of tetracycline or doxycycline in zymographic gels elicited an inhibition constant (IC50) of 278 +/- 10 microM and indicated that majority of MMP in the infarcted tissue is from fibroblast cells. The HHF proliferation was measured using an acid-phosphatase assay. The EDP and CDP induce HHF cell proliferation. After EDP treatment phenotypic (formation of pseudopodia) changes were observed in HHF cells. To measure whether phenotypic changes by EDP or CDP are associated with MMP and tissue inhibitor of metalloproteinase (TIMP) expression in HHF cells, we measured MMP and TIMP expression by zymographic and Northern blot (mRNA) analyses. The expression of MMP and TIMP were upregulated at both the protein and gene transcription levels. These results suggested that during ischemic cardiomyopathy, initially neutrophil proteinase activates latent myocardial MMP which can degrade ECM, which continuously degrades if not controlled by TIMP, leading to ventricular dilatation and dysfunction.
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PMID:Extracellular matrix regulation of metalloproteinase and antiproteinase in human heart fibroblast cells. 869 31

Cardiac hypertrophy occurs in a number of disease states associated with chronic increases in cardiac work load. Although cardiac hypertrophy may initially represent an adaptive response of the myocardium, ultimately, it often progresses to ventricular dilatation and heart failure. Much investigation has focused on the signaling pathways controlling cardiac hypertrophy at the level of the single cardiac myocyte. One prohypertrophic pathway that has received much attention involves the ubiquitously expressed Ca2+/calmodulin-activated phosphatase calcineurin. Upon activation by Ca2+, calcineurin dephosphorylates nuclear factor of activated T cell (NFAT) transcription factors, leading to their nuclear translocation. As common in complex biological systems, cardiac hypertrophy is controlled simultaneously by stimulatory (prohypertrophic) and counter-regulatory (antihypertrophic) pathways. Given the potent prohypertrophic effects of the Ca2+-calcineurin-NFAT pathway in cardiac myocytes, it is not surprising that the activity of this pathway is tightly controlled at multiple levels. Inhibitory mechanisms upstream (nitric oxide (NO), cGMP, cGMP-dependent protein kinase type I (PKG I), heme oxygenase-1 (HO-1), biliverdin, carbon monoxide (CO)) and downstream from calcineurin (glycogen synthase kinase-3 (GSK3), c-Jun N-terminal kinases (JNKs), p38 mitogen-activated protein kinase (MAPKs)) have been described. Moreover, several inhibitors directly target calcineurin enzymatic activity (cyclosporine A (CsA), tacrolimus (FK506), calcineurin-binding protein-1 (Cabin-1)/calcineurin-inhibitory protein (Cain), A-kinase-anchoring protein-79 (AKAP79), calcineurin B homology protein (CHP), MCIPs, VIVIT). Considering the dominant role of the calcineurin pathway in cardiac hypertrophy and failure, calcineurin-inhibitory strategies may lead to the identification of novel therapeutic approaches for patients with cardiac disease.
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PMID:Interference of antihypertrophic molecules and signaling pathways with the Ca2+-calcineurin-NFAT cascade in cardiac myocytes. 1527 70