The hypothesis to be tested here is that interventions following trauma that increase the glycosylation of nucleocytoplasmic proteins in cardiomyocytes decrease the cellular damage that would otherwise contribute to hypovolemic circulatory collapse. Our preliminary data demonstrate that in a rat model of hypovolemic stress, the infusion of glucosamine leads to a striking improvement in post-trauma function. We also demonstrate that glucosamine is protective in isolated heart models of ischemia/reperfusion and calcium overload. We propose that this protection results from an amplification of a natural, stress-activated, pro-survival pathway triggered by increased flux through the hexosamine biosynthesis pathway (HBP). The capacity to transduce an increase in the HBP's primary product, UDP-GIcNAc, into complex cellular responses comes about because O-GIcNAc transferase (OGT) is activated and recognizes distinct proteins as levels of UDP-GIcNAc increase. The identification of heat shock protein (HSP)-70 as an HBP-induced protein substrate for the OGT and the finding that HSP's associate with other proteins in part based on their ability to bind O-GIcNAc position this pathway at the center of a primary cellular response to stress. In support of this central role for O-GIcNAc in cellular protection, it is now clear that various stresses lead to increases in levels of both UDP-GIcNAc and protein-associated O-GIcNAc. We suggest that interventions that amplify and/or accelerate increases in O-GIcNAc greatly decrease the damage resulting from stress, particularly hypovolemic stress.
Our Specific Aims are: to optimize recovery in the rat model of hypovolemic stress through interventions that increase UDP-GIcNAc and to test the efficacy of these interventions in swine; to test the hypothesis that the mechanism by which increased UDP-GIcNAc leads to its ameliorating effects is because of an increase in O-GIcNAc on nuclear and cytoplasmic proteins; to document and identify the nucleocytoplasmic proteins in the heart that are preferentially derivatized with O-GIcNAc when protection is optimized in the hypovolemic rat model; to investigate the decrease in calcium influx seen with increased UDP-GIcNAc in mediating improved recoveries.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076175-02
Application #
6843142
Study Section
Special Emphasis Panel (ZHL1-CSR-I (F1))
Program Officer
Liang, Isabella Y
Project Start
2004-02-01
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
2
Fiscal Year
2005
Total Cost
$362,500
Indirect Cost
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Nöt, Laszlo G; Brocks, Charlye A; Vámhidy, Laszlo et al. (2010) Increased O-linked beta-N-acetylglucosamine levels on proteins improves survival, reduces inflammation and organ damage 24 hours after trauma-hemorrhage in rats. Crit Care Med 38:562-71
Chatham, John C; Marchase, Richard B (2010) The role of protein O-linked beta-N-acetylglucosamine in mediating cardiac stress responses. Biochim Biophys Acta 1800:57-66
Chatham, John C; Marchase, Richard B (2010) Protein O-GlcNAcylation: A critical regulator of the cellular response to stress. Curr Signal Transduct Ther 5:49-59
Zou, Luyun; Yang, Shaolong; Champattanachai, Voraratt et al. (2009) Glucosamine improves cardiac function following trauma-hemorrhage by increased protein O-GlcNAcylation and attenuation of NF-{kappa}B signaling. Am J Physiol Heart Circ Physiol 296:H515-23
Shan, Dan; Marchase, Richard B; Chatham, John C (2008) Overexpression of TRPC3 increases apoptosis but not necrosis in response to ischemia-reperfusion in adult mouse cardiomyocytes. Am J Physiol Cell Physiol 294:C833-41
Fulop, Norbert; Feng, Wenguang; Xing, Dongqi et al. (2008) Aging leads to increased levels of protein O-linked N-acetylglucosamine in heart, aorta, brain and skeletal muscle in Brown-Norway rats. Biogerontology 9:139-51
Xing, Dongqi; Feng, Wenguang; Not, Laszlo G et al. (2008) Increased protein O-GlcNAc modification inhibits inflammatory and neointimal responses to acute endoluminal arterial injury. Am J Physiol Heart Circ Physiol 295:H335-42
Chatham, John C; Not, Laszlo G; Fulop, Norbert et al. (2008) Hexosamine biosynthesis and protein O-glycosylation: the first line of defense against stress, ischemia, and trauma. Shock 29:431-40
Champattanachai, Voraratt; Marchase, Richard B; Chatham, John C (2008) Glucosamine protects neonatal cardiomyocytes from ischemia-reperfusion injury via increased protein O-GlcNAc and increased mitochondrial Bcl-2. Am J Physiol Cell Physiol 294:C1509-20
Liu, Jia; Marchase, Richard B; Chatham, John C (2007) Glutamine-induced protection of isolated rat heart from ischemia/reperfusion injury is mediated via the hexosamine biosynthesis pathway and increased protein O-GlcNAc levels. J Mol Cell Cardiol 42:177-85

Showing the most recent 10 out of 13 publications