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Vascular Medicine Institute

VMI

Sruti Shiva, Ph.D.

Sruti Shiva

Assistant Professor
Department of Pharmacology & Chemical Biology

E1242 BST
200 Lothrop Street
Pittsburgh, PA 15261

Phone: 412-383-5854
Lab Phone: 412-624-0462
Fax: 412-648-5980
Email: sss43@pitt.edu

Bio

Dr. Shiva received her Ph.D. from the University of Alabama, Birmingham in 2004.  After four years as a postdoctoral fellow at the National Heart Lung and Blood Institute, NIH, she moved to the University of Pittsburgh in 2008.

Research Interests

Dr. Shiva’s lab focuses on the mechanisms by which reactive nitrogen species (particularly nitrite and nitric oxide) regulate mitochondrial function during hypoxia and ischemia, the factors that influence this regulation and the implications of this regulation on pathology such as ischemia/reperfusion injury.

Active projects in her lab include:

The role of heme proteins in regulating nitrite-dependent modulation of mitochondrial respiration.  The anion nitrite (NO2-) is an endocrine storage form of nitric oxide (NO) in blood and tissues that can be reduced to bioavailable NO by heme proteins in conditions of low oxygen.  In blood, the reduction of nitrite by hemoglobin mediates hypoxic vasodilation.   We are interested in understanding how tissue nitrite reductases regulate mitochondrial function.  Specifically, myoglobin , when deoxygenated, can efficiently reduce nitrite to NO and this NO subsequently inhibits mitochondrial respiration by binding to complex IV of the mitochondrial respiratory chain.  We are interested in other ways that this interaction between nitrite and myoglobin regulates mitochondrial function as well as characterizing the physiological interplay between mitochondria and myoglobin with nitrite/NO acting as a signaling molecule linking the two.

The regulation of mitochondrial function by nitrite during ischemia/reperfusion.  Low concentrations of nitrite have been shown to mediate cytoprotection in a number of models of ischemia/reperfusion of the brain, liver, heart and kidney.  However, the mechanism of this cytoprotection is not known.  The mitochondria play a central role in the progression of ischemia/reperfusion injury.  Hence, we are interested in how nitrite regulates mitochondrial function during ischemia/reperfusion.   We have recently demonstrated that nitrite administered to animals before or during ischemia/reperfusion modulates mitochondrial function by S-nitrosating thiols on mitochondrial complex I, which leads to decreased reactive oxygen species generation, less oxidative damage of mitochondrial proteins, and prevention of cytochrome c release.  We think that these modifications of function prevent mitochondrial dysfunction after reperfusion and lead to cytoprotection. 

Figure 1

We are currently using isolated mitochondria, the Langendorff isolated and perfused heart, and in vivo ischemia/reperfusion models to further characterize nitrite-dependent cytoprotection, particularly in relation to other cytoprotective programs, such as ischemic preconditioning.

Mechanisms of nitrite generation and metabolism.  Another focus of the lab is determining the mechanisms by which nitrite is formed and metabolized physiologically.  Conventionally, nitrite is thought to be formed by the oxidation of nitric oxide.  However, in vivo, the reaction of nitric oxide with oxygenated hemoglobin (which produces nitrate) is more kinetically favorable than the reaction with oxygen to produce nitrite.  We have recently identified a role for the multicopper oxidase, ceruloplasmin, as an “NO oxidase” that can compete with the nitric oxide-hemoglobin reaction to oxidize NO to nitrite.  We are currently further characterizing the role of ceruloplasmin in regulating nitrite levels in physiology and pathology, and in plasma and tissue.

Figure 2

Key Publications

Shiva S. Mitochondria as metabolizers and targets of nitrite. Nitric Oxide (2010) 22(2):64-74.

Murillo D, Kamga C, Mo L, Shiva S. Nitrite as a mediator of ischemic preconditioning and cytoprotection. Nitric Oxide. (2011 Jan 26)

Shiva S, Rassaf T, Patel RP, Gladwin MT. The detection of the nitrite reductase and NO-generating properties of haemoglobin by mitochondrial inhibition. Cardiovasc Res. (2011) 89(3):566-73.

Shiva S, Sack MN, Greer JJ, Duranski M, Ringwood LA, Burwell L, Wang X, Macarthur PH, Raghavachari N, Calvert JW, Brookes PS, Lefer DJ, Gladwin MT.  Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J Exp Med.  Sep 3;204(9):2089-102 (2007).

Shiva S, Wang X, Ringwood LA, Xu X, Yuditskaya S, Annavajjhala V, Miyajima H, Hogg N, Harris ZL, Gladwin MT. Ceruloplasmin is a nitric oxide oxidase and nitrite synthase that determines endocrine NO homeostasis.  Nat. Chem. Bio. Sep;2(9):486-93 (2006).

Shiva S, Huang Z, Grubina R, Ringwood LA, MacArthur PH, Xu X, Darley-Usmar VM, Gladwin MT.  Deoxymyoglobin is a nitrite reductase that generates NO and regulates mitochondrial function. Circ. Res. Mar 16;100(5):654-61 (2007).

Shiva S and Venkatraman A, Wigley A, Ulasova E, Chhieng D, Bailey SM, Darley-Usmar VM. The role of iNOS in alcohol-dependent hepatotoxicity and mitochondrial function.  Hepatology Sept; 40(30): 565-73 (2004).

Shiva S, Crawford JH, Ceaser EK, Hillson T, Brookes PS, Patel RP, Darley-Usmar VM. Mechanisms of the interaction of nitroxyl with mitochondria.  Biochem. J. Jan 15 (2004).

Shiva S, Brookes PS, Patel RP, Anderson PG, and Darley-Usmar VM. Nitric Oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase. Proc. Natl. Acad. Sci. USA. 98(13):7212-7 (2001).

 

Shiva Lab

NO Metabolomics Facility

Pubmed link

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