Myoglobin is a monomeric, cytoplasmic hemoprotein expressed exclusively in cardiomyocytes and oxidative skeletal myofibers. The current paradigm proposes that myoglobin's sole functional role is to mediate oxygen transport within the heart in order to maintain oxidative phosphorylation for myocardial contractility. However, additional functions for myoglobin have been proposed including the role as a cytoprotective protein against reactive oxygen species and as a modulator of nitric oxide (NO). Our laboratory has engineered myoglobin knockout (Mb-/-) mice that are viable and have preserved cardiac function under normoxic conditions due to various cellular and molecular adaptations. We have shown that under chronic hypoxic conditions the Mb-/-mice develop left ventricular (LV) systolic dysfunction due to a NO-mediated, cGMP-independent mechanism. We have also demonstrated that over-expression of myoglobin in the mouse heart confers resistance to ischemic injury. Our overall hypothesis is that myoglobin serves cardioprotective roles in the heart by facilitating oxygen transport and regulating nitric oxide homeostasis within the cardiomyocyte. We will use our genetically modified mouse models to more fully characterize the regulation and function of myoglobin in the heart. Since evidence from human studies suggests there may be dysregulation of myoglobin expression in the failing human heart, our ultimate goal is to determine if augmentation of myoglobin expression and activity can be of therapeutic benefit in heart failure. To enhance our understanding of the regulation and functional roles of myoglobin in the heart, we propose the following three specific aims: 1) To define the mechanism underlying hypoxia-induced LV systolic dysfunction in the myoglobin null mice. 2) To define the cardioprotective mechanism(s) of myoglobin in the heart. 3) To define the transcriptional regulation of myoglobin gene expression under hypoxic conditions. The proposed experiments are hypothesis-driven and will determine the transcriptional regulation and functional roles of myoglobin in the heart. Ultimately, an enhanced understanding of myoglobin biology will provide opportunities for the development of new therapeutic measures in the treatment of patients with advanced heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL076440-05
Application #
7643830
Study Section
Special Emphasis Panel (ZHL1-CSR-B (M2))
Program Officer
Carlson, Drew E
Project Start
2005-09-30
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
5
Fiscal Year
2009
Total Cost
$108,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Singh, Sarvjeet; Canseco, Diana C; Manda, Shilpa M et al. (2014) Cytoglobin modulates myogenic progenitor cell viability and muscle regeneration. Proc Natl Acad Sci U S A 111:E129-38
Thibodeau, J T; Rao, M P; Gupta, C et al. (2013) Health insurance as a requirement to undergo cardiac transplantation: a national survey of transplant program practices. Transplant Proc 45:360-3
Quintens, Roel; Singh, Sarvjeet; Lemaire, Katleen et al. (2013) Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity and insulin resistance. PLoS One 8:e56719
Mishkin, Joseph D; Enriquez, Jonathan R; Meyer, Dan M et al. (2012) Utilization of cardiac computed tomography angiography for the diagnosis of left ventricular assist device thrombosis. Circ Heart Fail 5:e27-9
Thibodeau, Jennifer T; Mishkin, Joseph D; Patel, Parag C et al. (2012) IIIB or not IIIB: a previously unanswered question. J Card Fail 18:367-72
Wu, Roland S; Gupta, Sachin; Brown, Robert N et al. (2010) Clinical outcomes after cardiac transplantation in muscular dystrophy patients. J Heart Lung Transplant 29:432-8
Patel, Parag C; Reimold, Sharon C; Araj, Faris G et al. (2010) Concentric left ventricular hypertrophy as assessed by cardiac magnetic resonance imaging and risk of death in cardiac transplant recipients. J Heart Lung Transplant 29:1369-79
Kanatous, Shane B; Mammen, Pradeep P A (2010) Regulation of myoglobin expression. J Exp Biol 213:2741-7
Patel, Parag C; Ayers, Colby R; Murphy, Sabina A et al. (2009) Association of cystatin C with left ventricular structure and function: the Dallas Heart Study. Circ Heart Fail 2:98-104
Singh, Sarvjeet; Manda, Shilpa M; Sikder, Devanjan et al. (2009) Calcineurin activates cytoglobin transcription in hypoxic myocytes. J Biol Chem 284:10409-21

Showing the most recent 10 out of 14 publications