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In murine ventricular myocytes, activation of mechanosensitive ion channels (MSCs) includes activation of non-selective cation currents and deactivation of inwardly rectifying potassium currents. Using pharmacological inhibitors and knockout models, we analyzed signaling steps that are critical to transduce the mechanical signal (stretch) into electrophysiological events (MSC). We provide evidence for an activation of NAD(P)H oxidase and NOS3 in response to stretch putatively via the angiotensin II receptor type 1. The involvement of superoxide and nitric oxide was verified by the block of MSC using specific scavengers (tiron and PTIO, respectively). Superoxide and nitric oxide are known to combine very rapidly to form peroxynitrite. Accordingly, MSC were blocked by the peroxynitrite scavenger uric acid and could be mimicked by application of exogenous peroxynitrite. Peroxynitrite formation may activate phospholipases generating amphipaths that modulates channel function via changing the curvature of the surrounding lipid bilayer. This conclusion is supported by our findings that MSC were suppressed by inhibitors of phospholipases but could be mimicked by exogenous phospholipases or by amphipaths (oleic acid, Triton X-100). 相似文献
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Husse B Sopart A Isenberg G 《American journal of physiology. Heart and circulatory physiology》2003,285(4):H1521-H1527
Mechanical load as stimulus for apoptosis and necrosis could be responsible for the loss of cardiomyocytes. Ventricular myocytes from young (3 mo) and old (14-24 mo) rats underwent cyclical mechanical stretch (CMS; 5% elongation, 1 Hz) for 24 h. Spontaneous apoptosis was in myocytes from young rats 0.33 +/- 0.12% and from old rats 1.05 +/- 0.35% [Tdt-mediated dUTP nick-end labeling (TUNEL) assay]; associated with a decrease of Bcl-2. CMS increased the apoptosis to 0.58 +/- 0.18% in myocytes from young rats. Western blot analysis showed that CMS reduced Bcl-2 and increased p53 (young rats). Bax was not changed by CMS. These were confirmed by cytochrome c release (31 +/- 13%) and by the enrichment of cytosolic nucleosomes (11 +/- 8%). CMS did not influence the apoptosis in myocytes from old rats (TUNEL assay, Bcl-2, Bax, or p53). CMS did not cause necrosis in myocytes from young rats. CMS increased the number of necrotic cells by showing the cell membrane rupture in myocytes from old rats (50 +/- 13% 5-hexadecanoylaminofluorescein-positive and 38 +/- 6% propidium iodide-positive cells) as well as by measuring the lactate dehydrogenase release. The results suggest that CMS-induced apoptosis in myocytes of young rats but necrosis in myocytes from old rats, which could be attributed to more stress sensitivity of cells from old rats. 相似文献
4.
Salt effects on histone IV conformation 总被引:4,自引:0,他引:4
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Mark W. Zimmerman Kelley E. McQueeney Jeffrey S. Isenberg Bruce R. Pitt Karla A. Wasserloos Gregg E. Homanics John S. Lazo 《The Journal of biological chemistry》2014,289(9):5904-5913
Protein-tyrosine phosphatase 4A3 (PTP4A3) is highly expressed in multiple human cancers and is hypothesized to have a critical, albeit poorly defined, role in the formation of experimental tumors in mice. PTP4A3 is broadly expressed in many tissues so the cellular basis of its etiological contributions to carcinogenesis may involve both tumor and stromal cells. In particular, PTP4A3 is expressed in the tumor vasculature and has been proposed to be a direct target of vascular endothelial growth factor (VEGF) signaling in endothelial cells. We now provide the first in vivo experimental evidence that PTP4A3 participates in VEGF signaling and contributes to the process of pathological angiogenesis. Colon tumor tissue isolated from Ptp4a3-null mice revealed reduced tumor microvessel density compared with wild type controls. Additionally, vascular cells derived from Ptp4a3-null tissues exhibited decreased invasiveness in an ex vivo wound healing assay. When primary endothelial cells were isolated and cultured in vitro, Ptp4a3-null cells displayed greatly reduced migration compared with wild type cells. Exposure to VEGF led to an increase in Src phosphorylation in wild type endothelial cells, a response that was completely ablated in Ptp4a3-null cells. In loss-of-function studies, reduced VEGF-mediated migration was also observed when human endothelial cells were treated with a small molecule inhibitor of PTP4A3. VEGF-mediated in vivo vascular permeability was significantly attenuated in PTP4A3-deficient mice. These findings strongly support a role for PTP4A3 as an important contributor to endothelial cell function and as a multimodal target for cancer therapy and mitigating VEGF-regulated angiogenesis. 相似文献
6.
Southall MD Isenberg JS Nakshatri H Yi Q Pei Y Spandau DF Travers JB 《The Journal of biological chemistry》2001,276(49):45548-45554
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N. S. JELVEZ SERRA H. F. GOULART M. F. TRIANA S. DOS SANTOS TAVARES C. I. M. ALMEIDA J. G. DA COSTA A. E. G. SANTANA J. J. ZHU 《Medical and veterinary entomology》2017,31(4):381-391
The stable fly, Stomoxys calcitrans (Diptera: Muscidae), is a worldwide pest of livestock. Recent outbreaks of stable flies in sugarcane fields in Brazil have become a serious problem for livestock producers. Larvae and pupae found inside sugarcane stems after harvesting may indicate that stable flies use these stems as potential oviposition or larval development sites. Field observations suggest that outbreaks of stable flies are associated with the vinasse and filter cake derived from biomass distillation in sugarcane ethanol production that are used as fertilizers in sugarcane fields. Adult stable flies are attracted to vinasse, which appears to present an ideal larval development site. The primary goal of the present study is to demonstrate the role of vinasse in influencing the sensory physiological and behavioural responses of stable flies, and to identify its associated volatile attractant compounds. Both laboratory and field studies showed that vinasse is extremely attractive to adult stable flies. Chemical analyses of volatiles collected revealed a wide range of carboxylic acids, alcohols, phenols and aldehydes as potential attractant compounds. These newly identified attractants could be used to develop a tool for the attractant‐baited mass trapping of stable flies in order to reduce infestations. 相似文献
9.
Dai S Jia Y Wu SL Isenberg JS Ridnour LA Bandle RW Wink DA Roberts DD Karger BL 《Journal of proteome research》2008,7(10):4384-4395
Thiolutin is a sulfur-based microbial compound with known activity as an angiogenesis inhibitor. Relative to previously studied angiogenesis inhibitors, thiolutin is a remarkably potent inducer of heat shock protein 27 (Hsp27) phosphorylation. This phosphorylation requires p38 kinase but is independent of increased p38 phosphorylation. To elucidate how thiolutin regulates Hsp27 phosphorylation and ultimately angiogenesis, Hsp27 was immunoprecipitated using nonphosphorylated and phospho-Ser78 specific antibodies from lysates of thiolutin treated and untreated human umbilical vein endothelial cells and analyzed by LC-MS. Separate LC-MS analyses of Lys-C, Lys-C plus trypsin, and Lys-C plus Glu-C digests provided 100% sequence coverage, including the identification of a very large 13 kDa Lys-C fragment using a special sample handling procedure (4 M guanidine HCl) prior to the LC-MS analysis to improve the large peptide recovery. The analysis revealed a novel post-translational modification of Hsp27 involving truncation of the N-terminal Met and acetylation of the penultimate Thr. Analysis of a Glu-C fragment containing two phosphorylation sites, Ser78 and Ser82, and a tryptic fragment containing the other phosphorylation site, Ser15, enabled quantitative stoichiometry of Hsp27 phosphorylation by LC-MS. The strategy revealed details of Hsp27 phosphorylation, including significant di-phosphorylation at both Ser78 and Ser82, that would be difficult to obtain by traditional approaches because oligomerization of the hydrophobic N-terminal region of the molecule prevents efficient enzymatic cleavage. The combination of Western blotting, immunoprecipation, and LC-MS provides a quantitative analysis of thiolutin-stimulated Hsp27 phosphorylation and further defines the role of Hsp27 in the antiangiogenic activities of thiolutin and related dithiolethiones. 相似文献
10.
DA LAGE C 《Archives d'anatomie microscopique et de morphologie expérimentale》1958,47(3):401-445