eNOS and H
– Modulated Signal Transduction




For many years, reactive oxygen species (ROS) were viewed as pathological molecules, implicated in disease states ranging from atherosclerosis to neurodegeneration. More recently, the stable ROS hydrogen peroxide (H2O2) has been identified as a physiological signaling molecule.  We have used the H2O2 biosensor HyPer2 to explore the intracellular signaling pathways connecting receptor activation with H2O2–dependent signaling to eNOS in endothelial cells and cardiac myocytes.


  • Kalwa H, Sartoretto J, Martinelli R, Romero N, Steinhorn B, Tao M, Ozaki K, Carman C, Michel T. A central role for hydrogen peroxide in P2Y1 ADP receptor-mediated cellular responses in vascular endothelium. Proc Natl Acad Sci USA 2014, Mar 4;111(9):3383-8. doi: 10.1073/pnas.1320854111. PDF
  • Shiroto T, Romero N, Sugiyama T, Sartoretto J, Kalwa H, Yan Z, Shimokawa H, Michel T. Caveolin-1 is a critical determinant of autophagy, metabolic switching, and oxidative stress in vascular endothelium.  PLoS ONE 2014, 9(2): e87871. doi:10.1371/journal.pone.0087871. PDF
  • Kalwa H, Sartoretto JL, Sartoretto S, and Michel T. Angiotensin-II and MARCKS: a hydrogen peroxide- and Rac1-dependent signaling pathway in vascular endothelium.  J Biol Chem 2012, 287: 29147-29158. PMID: 22773836. PDF
  • Sartoretto JL, Kalwa H, Shiroto T,  Pluth M, Lippard S and Michel T.  Role of Ca2+ in the control of H2O2-modulated phosphorylation pathways leading to eNOS activation in cardiac myocytes. PLOS ONE  2012, 7(9): e44627. doi:10.1371/journal.pone.0044627. PMID: 22970272. PDF
  • Jin B, Lin AJ, Golan DE and Michel T. MARCKS protein mediates hydrogen peroxide regulation of endothelial permeability. Proc Natl Acad Sci USA 2012, 109 (37) 1486414869. PMID: 22927426. PDF
  • Sartoretto J, Kalwa H, Pluth M, Lippard S and Michel T.  Hydrogen peroxide differentially modulates cardiac myocyte nitric oxide synthesis.  Proc Natl Acad Sci USA 2011, 108: 15792-15797. PDF
  • Kou R, Shiroto T, Sartoretto JL and Michel T. Suppression of Gs synthesis by simvastatin in vascular endothelial cells.  J Biol Chem 2012, 287:2643-51.
  • Michel T.  NO way to relax : the complexities of coupling nitric oxide synthase pathways in the heart.  Circulation 2010, 121:484-486. PDF
  • Jin B, Sartoretto J, Gladyshev V, and Michel T.  Endothelial nitric oxide synthase negatively regulates hydrogen peroxide-induced AMP-activated protein kinase activation in endothelial cells. Proc Natl Acad Sci USA 2009, 106:17343-17348. PDF
  • Kou R, Sartoretto J and Michel T. Regulation of Rac1 by simvistatin in endothelial cells: differential roles of AMP-activated protein kinase and calmodulin-dependent kinase kinase-ß. J Biol Chem 2009, 14734-14743. PDF
  • Sugiyama T and Michel T.  Thiol-metabolizing proteins and endothelial redox state: Differential modulation of eNOS and biopterin pathways.  Am J Physiol Heart Circ Phys 2010, 298: H194-H201. PDF
  • Sugiyama T, Levy B and Michel T. Tetrahydrobiopterin recycling: a key determinant of eNOS-dependent signaling pathways in vascular endothelium. J Biol Chem 2009, 12691-12700. PDF
  • Kou R, Michel T. Epinephrine regulation of the endothelial isoform of nitric-oxide synthase: Roles of RAC1 and beta3-adrenergic receptors in endothelial NO signaling. J Biol Chem. 2007;282:32719-32729. PDF
  • Levine YC, Li GK, Michel T. Agonist-modulated regulation of AMP-activated protein kinase in endothelial cells: Evidence for an AMPK RAC1 AKT eNOS pathway. J Biol Chem. 2007; 282:20351-20364. PDF
  • Erwin PA, Mitchell D, Marletta M, Michel T. Subcellular targeting and S-nitrosylation of endothelial nitric oxide synthase. J Biol Chem. 2006;281:151-7. PDF
  • Gonzalez E, Kou R, Michel T. Rac1 and modulation of P13-kinase pathways in vascular endothelial cells. J Biol Chem. 2006;281:3210-6. PDF