Dept of Physiology, University of Calgary, Canada
The research in my laboratory is dedicated to a better understanding of the role of oxidative and nitrosative stress in vascular smooth muscle biology and cardiovascular disease.
Regulation of NO bioactivity in the vasculature. Nitric oxide (NO) is a small diatomic gaseous molecule that plays an essential role in regulating vascular physiology and pathophysiology. It is generated by a family of enzyme termed nitric oxide synthase (NOS) and regulates many aspects of vascular smooth muscle cell physiology. Although the means by which NO is produced and exert its effect have been characterized to a great extent, the mechanism by which NO is cleared and its signaling turned-off in the vascular wall is poorly understood. To understand how the vessel wall inactivates NO, we have focused our attention on Cytoglobin (Cygb), a new member of the globin vertebrate family with no known function.
This laboratory was the first to characterize the expression of Cygb in intact vessels and in vascular smooth muscle cells. We were also the first to demonstrate that Cygb contribute to NO inactivation and is solely responsible for basal production of inactive nitrate, one of the breakdown metabolite of NO. We are using a variety of molecular and biochemical approaches to further understand the role of Cygb in regulating smooth muscle cell function and NO bioactivity.
Nitrosation pathways and protein nitrosation. Increased rates of reactive nitrogen and oxygen species in tissues mediate the oxidation and nitrosation of protein amino acid residues. In many cases, these protein modifications are associated with a change or an impairment of protein structure and function. Our limited knowledge of how and which modifications of specific amino acid residues occur in vivo and how this is linked to protein dysfunction presently hinders the development of a causal relationship between these posttranslational protein modifications and tissue dysfunction. We have already identified a role for the free radical superoxide and the enzyme superoxide dismutase in regulating many of these modifications. Our overall objective is to provide a chemical foundation to understand the effects of NO in physiology and pathophysiology, focusing on nitrosation reactions. These studies ecompass proteomics, chemistry, and molecular approaches and have many implications related not only to vascular biology but also to cancer.
Techniques from chemistry to vascular physiology are being used.
- Free radical biochemistry: spectroscopic, chemiluminescence, and electrochemical methods and kinetic studies for the determination of reactive oxygen and nitrogen species.
- Molecular biology: cloning, mutagenesis, adenoviral and lentiviral expression systems.
- Cell biology: mammalian transfection, dual-emission fluorescence microscopy, laser scanning confocal fluorescence microscopy.
- Physiology: vasoreactivity studies of small and large arteries; animal models of vascular injuries and cardiovascular disease.
- Nitric Oxide in Vascular Smooth Muscle Biology.
- Inflammation and Oxidative Stress in Cardiovascular Disease.
- Biological Chemistry of Nitric Oxide.
- Ginnan R, Guikema B, Jourd’heuil FL, Simons M, Singer HA, and Jourd’heuil D. NADPH Oxidase 4 is required for interleukin-1?-mediated activation of protein kinase C? and downstream activation of c-Jun N-terminal kinase in smooth muscle. Free Rad. Biol. Med. 54:125-34, 2013. PMID: 23022406
- Redox-sensitivity and site-specificity of s- and N- denitrosation in proteins. Jourd'heuil FL, Lowery AM, Melton EM, Mnaimneh S, Bryan NS, Fernandez BO, Park JH, Ha CE, Bhagavan NV, Feelisch M, Jourd'heuil D. PLoS One. 2010 Dec 21;5(12):e14400.
- Lu, Q, Jourd’heuil FL, and Jourd’heuil D. Redox control of p53/p21cip/waf1 and cyclin D1/pRb during nitric oxide-mediated G0/G1 cell cycle arrest. J. cell. Physiol. 212:827-39, 2007
- Halligan KE, Jourd’heuil FL, and Jourd’heuil D. Cytoglobin is expressed in the vasculature and regulates cell respiration and proliferation via nitric oxide dioxygenation. J. Biol. Chem. 284(13):8539-8547, 2009.
- Trebak M., Ginnan R., Singer HA, and Jourd’heuil D. Interplay between calcium and reactive oxygen/nitrogen species: an essential paradigm for vascular smooth muscle signaling. Antioxid & Redox Signal. 12(5):657-74, 2010.