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Articles by U. M Chandrasekharan
Total Records ( 2 ) for U. M Chandrasekharan
  J Shen , U. M Chandrasekharan , M. Z Ashraf , E Long , R. E Morton , Y Liu , J. D Smith and P. E. DiCorleto
 

Rationale: Multiple protein kinases have been implicated in cardiovascular disease; however, little is known about the role of their counterparts: the protein phosphatases.

Objective: To test the hypothesis that mitogen-activated protein kinase phosphatase (MKP)-1 is actively involved in atherogenesis.

Methods and Results: Mice with homozygous deficiency in MKP-1 (MKP-1–/–) were bred with apolipoprotein (Apo)E-deficient mice (ApoE–/–) and the 3 MKP-1 genotypes (MKP-1+/+/ApoE–/– ; MKP-1+/–/ApoE–/– and MKP-1–/–/ApoE–/–) were maintained on a normal chow diet for 16 weeks. The 3 groups of mice exhibited similar body weight and serum lipid profiles; however, both MKP-1+/– and MKP-1–/– mice had significantly less aortic root atherosclerotic lesion formation than MKP-1+/+ mice. Less en face lesion was observed in 8-month-old MKP-1–/– mice. The reduction in atherosclerosis was accompanied by decreased plasma levels of interleukin-1 and tumor necrosis factor , and preceded by increased antiinflammatory cytokine interleukin-10. In addition, MKP-1–null mice had higher levels of plasma stromal cell–derived factor-1a, which negatively correlated with atherosclerotic lesion size. Immuno-histochemical analysis revealed that MKP-1 expression was enriched in macrophage-rich areas versus smooth muscle cell regions of the atheroma. Furthermore, macrophages isolated from MKP-1–null mice showed dramatic defects in their spreading/migration and impairment in extracellular signal-regulated kinase, but not c-Jun N-terminal kinase and p38, pathway activation. In line with this, MKP-1–null atheroma exhibited less macrophage content. Finally, transplantation of MKP-1–intact bone marrow into MKP-1–null mice fully rescued the wild-type atherosclerotic phenotype.

Conclusion: These findings demonstrate that chronic deficiency of MKP-1 leads to decreased atherosclerosis via mechanisms involving impaired macrophage migration and defective extracellular signal-regulated kinase signaling.

  W Zhu , U. M Chandrasekharan , S Bandyopadhyay , S. M Morris , P. E DiCorleto and V. S. Kashyap
 

Arterial thrombosis is a common disease leading to severe ischemia beyond the obstructing thrombus. Additionally, endothelial dysfunction at the site of thrombosis can be rescued by l-arginine supplementation or arginase blockade in several animal models. Exposure of rat aortic endothelial cells (RAECs) to thrombin upregulates arginase I mRNA and protein levels. In this study, we further investigated the molecular mechanism of thrombin-induced arginase changes in endothelial cells. Thrombin strikingly increased arginase I promoter and enzyme activity in primary cultured RAECs. Using different deletion and point mutations of the promoter, we demonstrated that the activating protein-1 (AP-1) consensus site located at –3,157 bp in the arginase I promoter was a thrombin-responsive element. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay further confirmed that upon thrombin stimulation, c-Jun and activating transcription factor-2 (ATF-2) bound to the AP-1 site, which initiated the transactivation. Moreover, loss-of-function studies using small interfering RNA confirmed that recruitment of these two transcription factors to the AP-1 site was required for thrombin-induced arginase upregulation. In the course of defining the signaling pathway leading to the activation of AP-1 by thrombin, we found thrombin-induced phosphorylation of stress-activated protein kinase/c-Jun-NH2-terminal kinase (SAPK/JNK or JNK1/2/3) and p38 mitogen-activated protein kinase, which were followed by the phosphorylation of both c-Jun and ATF-2. These findings reveal the basis for thrombin induction of endothelial arginase I and indicate that arginase inhibition may be an attractive therapeutic alternative in the setting of arterial thrombosis and its associated endothelial dysfunction.

 
 
 
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