Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endostatin, the COOH-terminal fragment of collagen XVIII, is a potent inhibitor of angiogenesis and tumor growth. To understand the mechanisms behind endostatin action, we analyzed the plasma membrane- extracellular matrix interactions of recombinant human endostatin in cultured microvascular endothelial cells. We observed that endostatin induced rapid clustering of alpha5beta1 integrin associated with actin stress fibers and its concomitant colocalization with the membrane anchor protein caveolin-1. Furthermore, endostatin could be coimmunoprecipitated with alpha5beta1 and caveolin-1 from endothelial cell extracts. Endostatin treatment induced phosphatase-dependent activation of caveolin-associated Src family kinases. The disassembly of actin stress fibers and focal adhesions by endostatin was found to occur via activation of Src and in a tyrosyl phosphatase-dependent manner. The endostatin-treated cells void of the focal adhesions had impaired ability to deposit fibronectin into their extracellular matrices and were unable to migrate in response to basic fibroblast growth factor in a wounding experiment. These results indicate that recombinant endostatin interacts with alpha5beta1 integrin and caveolin-1 at the endothelial cell surface. In addition, the antimigratory effect of endostatin involves phosphatase-dependent Src activation and impaired cell-matrix interactions.
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PMID:Endostatin associates with integrin alpha5beta1 and caveolin-1, and activates Src via a tyrosyl phosphatase-dependent pathway in human endothelial cells. 1235 71

Endothelial cell apoptosis is intimately involved in the balance between blood vessel growth and regression and is promoted by numerous stimuli including angiostatin and endostatin, reactive oxygen species (ROS) released during inflammatory processes, and chronic use of drugs of abuse such as cocaine. Apoptosis is characterized by many biological signalling events, including the activation of caspases. Caveolar domains have been hypothesized to mediate apoptotic signalling. We have addressed this hypothesis in cardiac endothelial cells and here we show that caspase-3 proenzyme (32 kDa) and its activated counterpart (17 kDa) co-purify with low-density, caveolin-enriched microdomains and that caspase-3 can be localized with caveolae in intact cells using fluorescent microscopy. Disruption of caveolae results in temporal and spatial changes in enzyme activity. While caspase-3 has been associated with mitochondrial, cytosolic, and high-density regions, the co-purification of activated caspase-3 and caveolar domains reported here suggests the possibility that sarcolemmal caspase-3 may be targeted to plasma-membrane associated substrates.
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PMID:Caveolar compartmentation of caspase-3 in cardiac endothelial cells. 1263 12

Severe pulmonary hypertension (SPH) is characterized by precapillary arteriolar lumen obliteration, dramatic right ventricular hypertrophy, and pericardial effusion. Our recently published rat model of SPH recapitulates major components of the human disease. We used this model to develop new treatment strategies for SPH. SPH in rats was induced using VEGF receptor blockade in combination with chronic hypoxia. A large variety of drugs used in this study, including anticancer drugs (cyclophosphamide and paclitaxel), the angiotensin-converting enzyme inhibitor lisinopril, the antiangiogenic agent thalidomide, and the peroxisome proliferator-actived receptor-gamma agonist PGJ2, failed to decrease mean pulmonary artery pressure (PAP) or right ventricular hypertrophy. In contrast, treatment of rats with established SPH with simvastatin markedly reduced mean PAP and right ventricular hypertrophy, and this reduction was associated with caspase-3 activation and pulmonary microvascular endothelial cell apoptosis. Simvastatin partially restored caveolin-1, caveolin-2, and phospho-caveolin expression in vessel walls. In rat primary pulmonary microvascular endothelial cells, simvastatin induced caspase 3 activation and Rac 1 expression while suppressing Rho A and attenuated levels of Akt and ERK phosphorylation. We conclude that simvastatin is effective in inducing apoptosis in hyperproliferative pulmonary vascular lesions and could be considered as a potential drug for treatment of human SPH.
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PMID:Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. 1669 53