Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammation contributes to the pathogenesis of atherosclerosis. Proinflammatory cytokines, including interleukin-1 (IL-1), may be involved in the local inflammation occurring in the vessel wall. Vascular smooth muscle cells express the unprocessed IL-1beta precursor molecule. Invading leukocytes, such as monocytes or polymorphonuclear granulocytes (PMN) may activate the IL-1beta precursor during atherogenesis. Thus, we investigated the capacity of PMN to process IL-1beta and IL-18 precursors. Processing was analyzed using Western blot and bioassay for IL-1-activity was performed. As few as 80 to 400 PMN/mL detectably processed preIL-1beta. PMN also cleaved the caspase-1 substrate preIL-18. The preIL-1beta and preIL-18 cleavage products were located at the same apparent molecular weight as those resulting from cleavage by monocyte-derived caspase-1. PMN expressed caspase-1 mRNA and immunoreactive protein. The N-terminus of the preIL-1beta cleavage product expressed the sequence expected for caspase-1 cleavage. The cleavage product was active in the bioassay for IL-1 activity, and the caspase-1 inhibitor YVAD blocked processing. We have shown previously that SMC can block processing of preIL-1 by caspase-1. In contrast, SMC do not block processing of PARP by caspase-3. Here, we show that SMC also inhibited the PMN-mediated processing of recombinant and native preIL-1beta or preIL-18 depending on the cell number, whereas EC or fibroblasts did not block processing. Our results indicate that PMN can activate preIL-1beta in a caspase-1-like fashion. During inflammatory processes, PMN may activate preIL-1beta released from SMC, thereby altering IL-1-mediated cardiovascular functions, including contractility, apoptosis, and cytokine production.
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PMID:Neutrophils process interleukin-1beta and interleukin-18 precursors in a caspase-1-like fashion--processing is inhibited by human vascular smooth muscle cells. 1661 59

Hyperglycemia has been shown to induce the p66shc expression leading to increased reactive oxygen species (ROS) generation and apoptosis. In the present study, we demonstrated that hyperglycemia induced p66shc expression in vascular smooth muscle cells. This induction was associated with an increase in apoptosis as assessed by the increase of capspase-3 enzymatic activity, cleaved caspase-3 protein, and the number of dead cells. The ability of IGF-I to inhibit apoptosis was also attenuated. Further studies showed that hyperglycemia-induced p66shc inhibited IGF-I-stimulated phosphoinositide (PI)-3 kinase and AKT activation. Mechanistic studies showed that knockdown of p66shc enhanced IGF-I-stimulated SHPS-1/p85, p85/SHP-2, and p85/Grb2 association, all of which are required for PI-3 kinase/AKT activation. These responses were attenuated by overexpression of p66shc. IGF-I-stimulated p85 and AKT recruitment to the cell membrane fraction was altered in the same manner. Disruption of p66shc-Src interaction using either a blocking peptide or by expressing a p66shc mutant that did not bind to Src rescued IGF-I-stimulated PI-3 kinase/AKT activation as well as IGF-I-dependent cell survival. Although the highest absolute level of ROS was detected in p66shc-overexpressing cells, the relative increase in ROS induced by hyperglycemia was independent of p66shc expression. Taken together, our data suggest that the increase in p66shc that occurs in response to hyperglycemia is functioning to inhibit IGF-I-stimulated signaling and that the incremental increase in SMC sensitivity to IGF-I stimulation that occurs in response to p66shc induction of ROS is not sufficient to overcome the inhibitory effect of p66shc on Src kinase activation.
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PMID:Hyperglycemia-induced p66shc inhibits insulin-like growth factor I-dependent cell survival via impairment of Src kinase-mediated phosphoinositide-3 kinase/AKT activation in vascular smooth muscle cells. 2053 22