Previously we have shown that extracellular (ex) heat shock protein (HSP)60 causes cardiac myocyte apoptosis and the synthesis of TNF and IL-1$. Blocking toll-like receptor (TLR)4 decreased, but did not abolish apoptosis, suggesting that the interaction of HSP60 with TLR4 is complex and involves other proteins. Our over-arching hypothesis is that HSP60 can cause apoptosis and inflammation, and this is associated with abnormal expression, distribution or post-translational modification of HSP60. We will expand our investigation in this important area with 3 specific aims designed to further define the role of HSP60 in heart failure and other cardiovascular disease. SA1 - Investigate the mechanism(s) of exHSP60 mediated apoptosis and inflammation. We will extend our investigation of TLR4 in exHSP60 signaling, determine whether, Eritoran, an inhibitor of TLR4, can reduce apoptosis in vitro and in vivo, and further characterize plasma membrane associated HSP60. SA2 - Investigate extracellular HSP60 trafficking and the role of post-translational modification in its toxicity. We hypothesize that post-translational modifications of HSP60 influence its localization and its extracellular toxicity. Studies have found high levels of HSP60 in the blood of patients with diabetes and other diseases. We will investigate the role of post- translational modifications as well as exosomes in the toxicity of this HSP60. Second we will examine the source of membrane associated HSP60. SA3 - Investigate the role of HSP60 in Repetitive Injury and the Heat Shock Paradox - The heat shock response is protective, and yet, when the heat shock response is induced after an inflammatory stress, rather than protection, increased injury occurs, hence. We found that HSP60 is increased after inflammation followed by heat shock, but not when the order of these stimuli is reversed. This increase in HSP60 is associated with increased apoptosis. In addition, blocking activated heat shock factor (HSF) decreased apoptosis. We will investigate the role of HSF1 and 2 in the heat shock paradox with selective knockout models. HSP60's role in the heat shock paradox will be studied by examining its cellular localization and manipulating its expression. The planned work will expand the PI's investigation of HSP60 and its role in cardiovascular inflammation and apoptosis and has the potential to lead to new therapeutic approaches to heart failure.

Public Health Relevance

We have shown that when HSP60 is outside the cell it causes heart cell death. The presence of HSP60 in the blood correlates with cardiovascular disease. We will investigate how HSP60 causes heart cell death, whether a new drug can block heart cell death, and whether changes to HSP60 make it more lethal. Lastly, we will investigate the how HSP60 exacerbates repetitive injury, which is very important in ICU patients and others, but seldom studied. These studies will enhance our understanding of cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079071-07
Application #
8496849
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2004-12-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
7
Fiscal Year
2013
Total Cost
$366,520
Indirect Cost
$128,520
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Lin, Li; Knowlton, Anne A (2014) Innate immunity and cardiomyocytes in ischemic heart disease. Life Sci 100:1-8
Rafizadeh, Sassan; Zhang, Zheng; Woltz, Ryan L et al. (2014) Functional interaction with filamin A and intracellular Ca2+ enhance the surface membrane expression of a small-conductance Ca2+-activated K+ (SK2) channel. Proc Natl Acad Sci U S A 111:9989-94
Knowlton, Anne A; Chen, Le; Malik, Zulfiqar A (2014) Heart failure and mitochondrial dysfunction: the role of mitochondrial fission/fusion abnormalities and new therapeutic strategies. J Cardiovasc Pharmacol 63:196-206
Liu, Tingting; Chen, Le; Kim, Eunjung et al. (2014) Mitochondrial proteome remodeling in ischemic heart failure. Life Sci 101:27-36
Chen, Le; Winger, Allison J; Knowlton, Anne A (2014) Mitochondrial dynamic changes in health and genetic diseases. Mol Biol Rep 41:7053-62
Malik, Z A; Kott, K S; Poe, A J et al. (2013) Cardiac myocyte exosomes: stability, HSP60, and proteomics. Am J Physiol Heart Circ Physiol 304:H954-65
Despa, Sanda; Margulies, Kenneth B; Chen, Le et al. (2012) Hyperamylinemia contributes to cardiac dysfunction in obesity and diabetes: a study in humans and rats. Circ Res 110:598-608
Knowlton, Anne A; Chen, Le (2012) Regulating a uniter: control of mitofusin 2 expression. Cardiovasc Res 94:6-7
Kobba, Samuel; Kim, Se-Chan; Chen, Le et al. (2011) The heat shock paradox and cardiac myocytes: role of heat shock factor. Shock 35:478-84
Gower, R Michael; Wu, Huaizhu; Foster, Greg A et al. (2011) CD11c/CD18 expression is upregulated on blood monocytes during hypertriglyceridemia and enhances adhesion to vascular cell adhesion molecule-1. Arterioscler Thromb Vasc Biol 31:160-6

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