Research Interests

The major source of “high-output” NO during inflammation is iNOS. It was widely accepted that iNOS is regulated primarily at the transcriptional level and, once expressed, generates unregulated high output NO. We have described a novel mode of post-translational, receptor-mediated increase in iNOS activity via phosphorylation at Ser745 (J Biol Chem. 2007 Nov 2;282(44):32453-61).  We were studying the signaling pathways that may lead to iNOS phosphorylation. We showed that stimulation of the B1 kinin G protein-coupled receptor (B1R) couples through Gαi and Gβγ to induce activation of Src, Ras, Raf and MEK, leading to ERK phosphorylation of Ser745 on iNOS resulting in a 3- to 5-fold further increase in NO production. In addition, we are studying the effect of acute activation of iNOS and superoxide production on barrier function of endothelial cells.

We hope that our studies will provide novel strategies for therapeutic intervention to improve endothelial barrier function in inflammatory lung injury.

• Mirza MK, Yuan J, Gao XP, Garrean S, Brovkovych V, Malik AB, Tiruppathi C, Zhao YY. Caveolin-1 Deficiency Dampens Toll-Like Receptor 4 Signaling through eNOS Activation. Am J Pathol. 2010 Mar 19. [Epub ahead of print]
  
  
• Kuhr FK, Zhang Y, Brovkovych V, Skidgel RA. {beta}-Arrestin 2 is required for B1 receptor-dependent post-translational activation of inducible nitric oxide synthase. FASEB J. 2010 Mar 17. [Epub ahead of print]
  
  
• Kuhr F, Lowry J, Zhang Y, Brovkovych V, Skidgel RA. Differential regulation of inducible and endothelial nitric oxide synthase by kinin B1 and B2 receptors. Neuropeptides. 2010 Apr;44(2):145-54. Epub 2010 Jan 4.
  
  
• Brovkovych V, Zhang Y, Brovkovych S, Minshall RD, Skidgel RA. A novel pathway for receptor-mediated post-translational activation of inducible nitric oxide synthase. J Cell Mol Med. 2009 Dec 10. [Epub ahead of print]
  
  
• Zhao YY, Zhao YD, Mirza MK, Huang JH, Potula HH, Vogel SM, Brovkovych V, Yuan JX, Wharton J, Malik AB. Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. J Clin Invest. 2009 Jul;119(7):2009-18.
  
  
• Marjanovic JA, Stojanovic A, Brovkovych VM, Skidgel RA, Du X. Signaling-mediated functional activation of inducible nitric-oxide synthase and its role in stimulating platelet activation. J Biol Chem. 2008 Oct 24;283(43):28827-34. Epub 2008 Aug 27.
  
  
• Brovkovych V, Gao XP, Ong E, Brovkovych S, Brennan ML, Su X, Hazen SL, Malik AB, Skidgel RA. Augmented inducible nitric oxide synthase expression and increased NO production reduce sepsis-induced lung injury and mortality in myeloperoxidase-null mice. Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L96-103. Epub 2008 Apr 18.
  
  
• Zhang Y, Brovkovych V, Brovkovych S, Tan F, Lee BS, Sharma T, Skidgel RA. Dynamic receptor-dependent activation of inducible nitric-oxide synthase by ERK-mediated phosphorylation of Ser745. J Biol Chem. 2007 Nov 2;282(44):32453-61. Epub 2007 Sep 5.