Cardiovascular disease is the major cause of morbidity and mortality in the United States. While varied in clinical presentation, it is generally assumed that inflammation is a common mechanism of cardiovascular disease pathogenesis. The vascular endothelium is the structural lining of all blood vessels that serves as an active barrier between the circulation and the surrounding tissue, and are increasingly recognized for vital participant in the inflammatory signaling cascade. A common mechanism by which endothelial cells (ECs) sense inflammatory signals is by an increase in intracellular calcium (Ca2+) via inositol 1,4,5-trisphosphate receptors (InsP3R) on the endoplasmic reticulum. Despite their ubiquitous presence in the vasculature, ECs display a great degree of heterogeneity in the InsP3R -mediated Ca2+ response dependent upon their vascular origin. Unfortunately, how heterogeneous Ca2+ signals are generated and how they impact endothelial function are unknown. The focus of my work has been to understand the delicate interaction between Ca2+ signals and mitochondria! function, and how this interaction impacts endothelial homeostasis. Recently, I have discovered that InsPSR -mediated Ca2+ transmits to the mitochondria, which 'decodes'these Ca2+ signals into reactive oxygen species (ROS) and endothelial inflammation. My preliminary findings suggest that ROS may selectively modify InsPSRs to mediate intracellular Ca2+ signaling. The short term goal of this project (K.99) is to investigate whether heterogeneous Ca2+ signaling is due to the selective modification of InsP3R type 1 and 2 in ECs. Under the mentorship of Drs. Aron Fisher and Madesh Muniswamy, the initial phase of this award will allow me to study the control of EC Ca2+ signaling by ROS, and also to provide me with the direction, laboratory facilities, and scientific structure necessary to advance my skills and transition into an independent investigator. The long term goal of this work (ROO) is to ultimately understand how mitochondrial ROS impacts EC Ca2+ signaling and triggers inflammatory signaling via the transcription factor NF-kB. While a correlative link between mitochondrial function, ROS production, and EC inflammation exists, a causative link between these variables has not been established. If a definitive link can be made, agents designed to counter specific InsPSR activity and mitochondrially-targeted antioxidant compounds may constitute an attractive therapeutic target during vascular inflammatory conditions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Career Transition Award (K99)
Project #
5K99HL094536-02
Application #
7770784
Study Section
Special Emphasis Panel (ZHL1-CSR-Z (O1))
Program Officer
Commarato, Michael
Project Start
2009-02-18
Project End
2010-08-01
Budget Start
2010-02-01
Budget End
2010-08-01
Support Year
2
Fiscal Year
2010
Total Cost
$90,000
Indirect Cost
Name
Temple University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Marcu, Raluca; Kotha, Surya; Zhi, Zhongwei et al. (2015) The mitochondrial permeability transition pore regulates endothelial bioenergetics and angiogenesis. Circ Res 116:1336-45
Marcu, Raluca; Wiczer, Brian M; Neeley, Christopher K et al. (2014) Mitochondrial matrix Ca²? accumulation regulates cytosolic NAD?/NADH metabolism, protein acetylation, and sirtuin expression. Mol Cell Biol 34:2890-902
Marcu, Raluca; Neeley, Chris K; Karamanlidis, Georgios et al. (2012) Multi-parameter measurement of the permeability transition pore opening in isolated mouse heart mitochondria. J Vis Exp :
Shuvaev, Vladimir V; Han, Jingyan; Yu, Kevin J et al. (2011) PECAM-targeted delivery of SOD inhibits endothelial inflammatory response. FASEB J 25:348-57
Davis, Christiana W; Hawkins, Brian J; Ramasamy, Subbiah et al. (2010) Nitration of the mitochondrial complex I subunit NDUFB8 elicits RIP1- and RIP3-mediated necrosis. Free Radic Biol Med 48:306-17
Hawkins, Brian J; Levin, Mark D; Doonan, Patrick J et al. (2010) Mitochondrial complex II prevents hypoxic but not calcium- and proapoptotic Bcl-2 protein-induced mitochondrial membrane potential loss. J Biol Chem 285:26494-505
Hawkins, Brian J; Irrinki, Krishna M; Mallilankaraman, Karthik et al. (2010) S-glutathionylation activates STIM1 and alters mitochondrial homeostasis. J Cell Biol 190:391-405
Potula, Raghava; Hawkins, Brian J; Cenna, Jonathan M et al. (2010) Methamphetamine causes mitrochondrial oxidative damage in human T lymphocytes leading to functional impairment. J Immunol 185:2867-76
Madesh, Muniswamy; Zong, Wei-Xing; Hawkins, Brian J et al. (2009) Execution of superoxide-induced cell death by the proapoptotic Bcl-2-related proteins Bid and Bak. Mol Cell Biol 29:3099-112
Levin, Mark D; Lu, Min Min; Petrenko, Nataliya B et al. (2009) Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers. J Clin Invest 119:3420-36