B C Berk

..Because TXNIP is an ?-arrestin that regulates VEGFR2 signaling, we hypothesized that PARP1 regulates TXNIP localization and function that might affect HUVEC stress-induced apoptosis...

..We previously showed that thioredoxin interacting protein (TXNIP) was required for tumor necrosis factor-mediated expression of vascular cell adhesion molecule-1...

..We suggest that modifying the redox state of the vasculature is an attractive therapeutic approach if we target specific redox dependent pathways such as TXNIP...

..In summary, relatively small alterations in redox (SOD-2) and NO pathways (eNOS and PKG) may contribute to significantly impaired vasorelaxation in SJL mice...

..Recent research suggests that therapies targeting the expression, synthesis, or activation of the enzymes responsible for ECM homeostasis might represent novel opportunities to modify the natural progression of HHD...

..This model should be useful to identify and characterize the role of genes that mediate vascular remodelling...

..In summary, the atheroprotective effects of steady laminar flow on the endothelium involve multiple synergistic mechanisms...

..Understanding the importance of tyrosine phosphorylation in AngII-stimulated signaling events may contribute to new therapies for cardiovascular and renal diseases...

..In this study, we identified specific GIT1 tyrosines required for PLC? activation and podosome formation in vascular smooth muscle cells (VSMC)...

..Although the complexity of ROS-mediated signal transduction is daunting, the diversity offers multiple therapeutic targets for pharmacologic intervention...

..Less is known about signaling through the AT2R, which often antagonizes the effects of signaling through the AT1R, but intriguing data are beginning to emerge concerning the signaling strategies and pathways that the AT2R employs...

..Thus, understanding AngII-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases...

..There is accumulating evidence that GPCR take advantage of signaling pathways downstream of RTK to exert its effect on the cells. In this context, RTK may be considered as one of signaling molecules downstream of GPCR...

..In addition, the differential inhibition of p90RSK and BMK1 in hearts with congestive heart failure suggests the specific role of these two kinases to maintain cardiac function under chronic pressure-overload...

..These data suggest important roles for Src family kinases and adenosine in mediating preconditioning, and suggest specific roles for individual MAP kinases in preconditioning...

..Inhibition of TNF-alpha signal transduction represents a mechanism by which steady laminar flow may exert atheroprotective effects on the endothelium...

..These data establish ASK1 as a target for flow-mediated inhibition of cytokine signaling and indicate a novel role for 14-3-3 as an anti-inflammatory mediator in ECs...

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..These results demonstrated the importance of Bcr in PDGF-mediated events such as activation of Ras, Raf-1, and ERK1/2 and stimulation of DNA synthesis...

..CONCLUSIONS: The present study indicates that performing a genetic cross of these strains and total genome scan should identify genes that mediate vascular remodeling...

..These data suggest that decreasing cholesterol content in caveolae by CsA is a potentially important pathogenic mechanism for CsA-induced endothelial dysfunction and hypertension...

..In summary, the present study further supports a key role for GIT1 (a MEK1-binding protein) as a scaffold for signal transduction in focal adhesions...

..Because steady laminar flow exerts an antioxidant effect, we hypothesized that Grx mediates flow induced Akt and eNOS phosphorylation in a GR dependent manner...

..These results suggest that BMK1 activation by steady laminar flow is atheroprotective by inhibiting EC apoptosis via phosphorylation of Bad...

..These data are the first to establish a critical role of Flk-1/KDR in S1P-stimulated eNOS phosphorylation and activation...

..These data establish S1P as an important stimulus for EGFR and PDGFbetaR activation in VSMCs that may have important implications for the vessel response to injury...

..CONCLUSIONS: These results show a redox-sensitive pathway for flow-mediated activation of nonreceptor tyrosine kinase activity that requires ROS and intracellular calcium, but not Src kinase...

..Because Bcr encodes a serine/threonine protein kinase, we studied its kinase activity and determined the role of Bcr in the PDGF signaling pathway to ERK1/2 activation and DNA synthesis in rat aortic smooth muscle cells (RASMCs)...

..The data suggest that TXNIP and TRX are key components of biomechanical signal transduction and establish them as potentially novel regulators of TNF signaling and inflammation in ECs...

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..Here, we characterized phenotypic traits related to carotid remodeling in the 2 rat strains that we previously showed the greatest difference in shear stress regulation: Genetically Hypertensive (GH) and Brown Norway (BN) rat strains...

..We propose that GIT1 serves as a scaffold protein to facilitate c-Src-dependent activation of MEK1-ERK1/2 in response to both GPCRs and TKRs...

..We propose that GIT1 is a novel regulator of PLCgamma function that mediates PLCgamma activation by c-Src and integrates signal transduction by GPCRs and TKRs...

..These results demonstrate an important difference in signal transduction by angII compared with PDGF and phorbol ester in VSMC, and suggest a critical role for PKC-zeta and Ras in angII stimulation of ERK1/2...

..This interaction provides a direct link between Axl and molecular motors crucial for directed cell migration, which may mediate increased migration in vascular dysfunction...

..This study emphasizes the important role of genetic factors in vascular remodeling and suggests that genetic analysis of these strains will provide novel insights into the underlying mechanisms...

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..Taken together our results show that PKC? binds and phosphorylates ERK5, thereby decreasing eNOS protein stability and contributing to early events of atherosclerosis...

..In summary, Axl is an important signaling mediator for oxidative stress in cultured vascular smooth muscle cells and intact vessels and may represent an important therapeutic target for vascular remodeling and response to injury...

..These results suggest that flow activates GR, an important regulator of the intracellular redox state of glutathione, and exerts a protective mechanism against oxidative stress in endothelial cells...

..Taken together, these observations indicate that ERK5 is regulated by distinct mechanisms determined by its unique structure and presumably the presence of multiple splice variants...

..Thus, understanding angiotensin II-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases...

..These results establish Tie2 transactivation via PECAM1 as an early event in flow-mediated mechanotransduction and suggest an important role for a PECAM1-SHP2-Tie2 pathway in flow-mediated signal transduction...

..Because the SJL strain is prone to autoimmune diseases, we hypothesized that inflammation contributed to IMT in SJL mice...

..These data suggest that Gab1-ERK1/2 binding and their nuclear translocation play a crucial role in Egr-1 nuclear accumulation...

..Furthermore, we identified a novel sequence for SHP-2/Gab1 interactions in the C-terminal region of SHP-2...

..CONCLUSIONS: These results suggest that physiological shear stress is antiinflammatory by specifically inhibiting MAP kinase signaling and inhibiting TRAF-2 interaction with TNFR-1...

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..These results suggest that SNAP and CNP exert inhibitory effects on NF-kappaB-dependent transcription by activation of PKA via cGMP-dependent inhibition of PDE3 activity. Therefore, PDE3 is a novel mediator of inflammation in VSMCs...

..CONCLUSIONS: The mouse model described here may be useful to define genetic determinants of IMT and identify new targets for therapy based on vascular remodeling...

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..Furthermore, the IGF-1-mediated downregulation of Gab1 expression represents a novel mechanism to promote vascular inflammation and atherosclerosis...

..c-Src kinase activity is required for the cytoskeletal turnover that occurs in cell spreading, whereas c-Src appears to regulate actin bundling via a kinase-independent mechanism...

..In conclusion, our data demonstrate that the PDGFbetaR and the EGFR form PDGFbetaR-EGFR heterodimers basally, and we suggest that heterodimers represent a novel signaling complex which plays an important role in PDGF signal transduction...

..These findings establish the Gas6-Axl-PI3K-Akt pathway as an anti-apoptotic mechanism for VSMC that may be important in the response to vascular injury...

..Because GIT1 is a substrate of c-Src, and podosome formation is c-Src dependent, we hypothesized that GIT1 plays an important role in VEGF-induced EC podosome formation and cell migration...

..Because PDGF-mediated ERK activation is enhanced in Chinese hamster ovary cells that overexpress Gab1, Gab1 serves as an important link between PKC and ERK activation by PDGFbeta receptors in VSMC...

..Inhibiting PDE1A1 expression and/or activity could be a novel therapeutic approach to limit nitrate tolerance...

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..Finally, PKB phosphorylated eNOS in vitro at the same site phosphorylated in the cell and increased eNOS enzymatic activity by 15-20-fold...

..Because tyrosine phosphorylation is a key regulatory pathway for VEGF-mediated endothelial cell (EC) responses, we investigated tyrosine phosphorylation of G6PD and the role of the nonreceptor tyrosine kinase Src...

..These data define a previously undescribed role for CypA in AAA formation and suggest CypA as a new target for treating cardiovascular disease...

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..However, there have been no in vivo studies of GIT1 function to date...

..These results support a key role for the MEK5-BMK1 signaling pathway in the atheroprotective effects of blood flow...

..These results establish a novel mechanism by which glucose-dependent EGFR N-glycosylation modulates AngII signal transduction and suggest a potential mechanism for pathogenic effects of AngII in diabetic vasculopathy...

..These data show that GIT1 is a key regulator of bone mass in vivo by regulating osteoclast function and suggest GIT1 as a potential target for osteoporosis therapy...

..Our findings define a novel VSMC vesicular secretory pathway for CyPA that involves actin remodeling and myosin II activation via RhoA-, Cdc42-, and Rho kinase-dependent signaling events...

..These data suggest that ERK5 mediates flow- and ligand-induced PPARgamma activation via the interaction of ERK5 with the hinge-helix 1 region of PPARgamma...

..In summary, flow-induced IMT of the carotid is genetically determined and correlates with t-PA and u-PA expression in 2 inbred mouse strains...

..These findings demonstrate that activation of BMK1 is different from ERK1/2 and suggest an important role for BMK1 as a redox-sensitive kinase...

..Finally, the heterogeneous nature of VSMC developmental origin provides another level of complexity in VSMC growth mechanisms...

..Our results implicate Axl as a potential mediator of vascular smooth muscle migration and proliferation caused by vascular injury and G protein-coupled receptor agonists...

..These studies are the first to define a PLC-gamma-associated protein that may be required for Ang II-mediated signal transduction...

..Finally, we show that inhibiting VEGFR2 kinase significantly reduces flow-mediated NO-dependent arteriolar dilation in vivo. These data identify VEGFR2 as a key mechanotransducer that activates eNOS in response to blood flow...

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..CyPA plays a crucial role in VSMC proliferation/migration and inflammatory cell recruitment, resulting in cardiovascular diseases in vivo...

..Furthermore, the contrasting responses in B6F and FB6 F(1) strains show that a maternal component strongly influences strain-dependent differences in training responses...

..We therefore studied the proinflammatory effects of CyPA on vascular endothelium...

..Here we investigated the hypothesis that Ang II-mediated vascular smooth muscle cell (VSMC) gene transcription involves GIT1-CamK II-dependent phosphorylation of HDAC5...

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..Finally, knockdown of endogenous Gab1 by small interference RNA abrogated flow activation of Akt and eNOS. These data demonstrate a critical role of Gab1 in flow-stimulated PI3K/Akt/eNOS signal pathway in endothelial cells...

..More comprehensive analyses of the specific molecular pathways in the vessels that determine constant flow may provide new therapeutic approaches to regulate vascular remodeling...

..Telemetered SBP measurements in conscious rats were highly variable in a strain-dependent manner...

..These data suggest that 14-3-3beta binding negatively regulates RSK1 activity to maintain signal specificity and that association/dissociation of the 14-3-3beta-RSK1 complex is likely to be important for mitogen-mediated RSK1 activation...

..These data demonstrate an important role for Axl in flow-dependent remodeling by regulating vascular apoptosis and vascular inflammation...

..These results show that brief oxidative stress causes sustained release of protein factors from VSMC that can stimulate ERK1/2. These factors may be important mediators for the effects of reactive oxygen species on vascular function...

..13 +/- 0.02 versus 0.48 +/- 0.06 mmol of H(+)/min/liter, p < 0.01). These data suggest that 14-3-3 binding to NHE1 participates in serum-stimulated exchanger activation, a new function for 14-3-3...

..atRA-mediated apoptosis in SMCs seems to require the participation of active tTG, suggesting a potential mechanistic link between this retinoid-inducible gene and programmed cell death...

..Thus, it is important to understand angiotensin II-mediated signaling events, especially those related to tyrosine kinase activity, to develop new therapies for cardiovascular diseases...

..Because TXNIP is an ?-arrestin with numerous protein-protein interacting domains, we hypothesized that TXNIP-TRX1 trafficking should alter function of EC exposed to reactive oxygen species (ROS)...

..In this study, we sought to evaluate the role of CyPA in Ang II-induced cardiac hypertrophy...

..Understanding the mechanisms by which steady laminar flow regulates JNK activation by cytokines may provide insight into the atheroprotective mechanisms induced by laminar blood flow...

..We propose that TRX and its endogenous regulators are important future targets to develop clinical therapies for cardiovascular disorders associated with oxidative stress...

..In summary, terminal arterioles are affected by nitrates to a greater extent than the arcade arterioles that feed them, in a process dependent on angiotensin II and ROS...

..In this article, we review the role of hypertension in the metabolic syndrome, its complex association with obesity and IR, and its disproportionate contribution to the syndrome in certain ethnic groups (specifically US blacks)...

..CONCLUSIONS: These data show that uPA is an autocrine VSMC growth factor that increases ROS generated by both Nox1 and Nox4 oxidases...

..S-nitrosylation of Trx also contributes to the anti-apoptotic function of Trx. Thus, Trx can exert its complete redox regulatory and anti-apoptotic functions in endothelial cells only when cysteine 69 is S-nitrosylated...

..Elucidating the tissue- and cell-specific pathways by which vessels remodel in response to low flow should provide insights for therapies to improve vascular function in atherosclerosis, hypertension, and stroke. ..

..These studies will provide new insight into the mechanisms by which ROS regulate vascular function and the specific role of CyPA in atherosclerosis. ..

..The proposed studies will provide insight into a novel scaffold protein that should be important both for AII signal transduction and MAP kinase function. ..

..The proposed studies will provide insight into a novel scaffold protein that should be important both for AII signal transduction and MAP kinase function. ..

..PUBLIC HEALTH RELEVANCE: The healing of tissues after surgery or trauma is critical for long-term survival. The proposed work will study novel mechanisms by which blood vessels grow in response to tissue injury. ..

..Elucidating the tissue- and cell-specific pathways by which cyclophilin A modulates atherogenesis would provide insights for therapies to improve vascular function in this disease. ..

..Elucidating the specific pathways by which protein kinase C-zeta modulates vessel function would provide the basis to develop new therapies to prevent atherosclerosis. ..

..PUBLIC HEALTH RELEVANCE: The healing of tissues after surgery or trauma is critical for long-term survival. The proposed work will study novel mechanisms by which blood vessels grow in response to tissue injury. ..

..We believe this will be an excellent Gordon Research conference based on the timeliness of the subject matter, the excellence of the organization and program content, the excellence of the proposed speakers, and the meeting facilities. ..

..These studies should provide insight into mechanisms by which flow inhibits vascular inflammation and facilitate development of new therapeutic approaches to limit atherosclerosis. ..

..This proposal represents the first step in elucidating the genetics of vascular remodeling which may yield new therapeutic approaches to diseases such as carotid and coronary atherosclerosis. ..

..The University of Rochester is a research-intensive institution with a long tradition and commitment to training investigators which should facilitate the success of this program in cardiovascular research. ..

..these studies should provide insight into the mechanisms by which ROS regulate remodeling and aid development of new therapeutic approaches to limit restenosis and atherogenesis. ..

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..Aim 3: Study the role of PDGF receptor tyrosine phosphorylation in fine domains of the AT I R required knowledge of the mechanisms by which AII exerts physiologic and pathologic effects on the cardiovascular system. ..

..These studies should provide insight into the mechanisms by which flow generates an atheroprotective signal and facilitate development of new therapeutic approaches to limit atherosclerosis. ..

..These studies will provide new insight into the mechanisms by which ROS regulate vascular function and the specific role of CyPA in atherosclerosis. ..

..The proposed studies will provide insight into a novel scaffold protein that should be important both for AII signal transduction and MAP kinase function. ..

..Aim 4. Create a congenic strain of GH rats containing genes associated with high remodeling ability. ..