Oxidative stress has been increasingly recognized as a common feature among different forms of heart disease. Elevated reactive oxygen species (ROS) has been shown as a convergent signaling messenger leading to failing heart either of ischemic or non-ischemic origin. Despite significant progress in many areas of ROS related investigations, two fundamental issues remain unresolved and will constitute the center of this proposed investigation. The first question is who are the regulators of ROS in the diseased myocardium? The second question is what are the molecular targets of ROS and how do ROS-induced molecular modifications result in cardiac dysfunction? This application is inspired by our exciting data identifying PP2Cm as a novel regulator of ROS;and by the intriguing preliminary evidence that the cardiac proteasome complexes are a new class of molecular targets for ROS. Accordingly, the proposed investigation will address a novel aspect of ROS signaling: its modulation by PP2Cm, and it will embark on a largely unexplored area of research: the functional consequences of ROS elevation--its impact on the proteasome systems and their substrates. The application will determine the emerging role of PP2Cm in ROS biology;it will establish proteasome subunits as a new set of molecular targets for the elevated ROS;and it will systematically characterize perturbed protein degradation pathways in the normal and stressed myocardium. Furthermore, the application will identify potential therapeutic windows whereby disrupted protein quality control may be rescued. To accomplish our goals, two related models of cardiac stress--pressure overload by transverse-aortic constriction (TAC) and myocardial ischemic injury (I/R)-are employed.
Three specific aims are proposed:
Aim 1 will elucidate mechanisms underlying PP2Cm mediated protection of the heart;it will determine its role in governing ROS regulation and examine the impact of genetic perturbations of PP2Cm in TAC and I/R using the newly established PP2Cm genetic models in-house (the null/LacZ knock-in KO and the cardiac conditional inducible Tet-Off).
Aim 2 will establish roles of the 20S and 26S proteasomes in the two stress models with respect to proteasome complex assembly, function, and degradation capacity;it will decipher molecular events underlying ROS damaged 20S and 26S proteasomes. It will apply a targeted proteomic approach to delineate the molecular modification of proteasome subunits;and it will define the functional significance of such modifications.
Aim 3 will define functional consequences of ROS-injured 20S and 26S proteasomes in the two pathological models;it will characterize the substrate repertoire of 20S and 26S proteasomes in the normal and stressed myocardium. Our research plan is supported by """"""""a technology tool box"""""""" combining established methods and innovative approaches assembled by the investigator team. It encompasses genetic models, proteasome biology, ROS biology, disease models, quantitative proteomics, and high-resolution imaging. Collectively, the proposed studies will conclusively characterize PP2Cm regulation of ROS in the stress myocardium;it will establish proteasome subunits as novel targets of ROS;and it will provide mechanistic insights into protein homeostasis in the two stress models.

Public Health Relevance

Our proposal addresses a novel hypothesis that oxidative stress in the diseased myocardium is regulated in part by a mitochondria specific protein phosphatase;and one important functional impact of the elevated levels of reactive oxygen species is the damage of cardiac proteasomes. The proposed investigation will gain insights on these diseases and will help to develop new therapeutic strategies to prevent or reverse pathological remodeling in the diseased myocardium. Therefore, our proposal has significant clinical relevance as well as potential key contributions to the fundamental knowledge of mitochondrial biology, ROS biology, proteasome biology, and their functional impact on the cardiovascular systems.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098954-03
Application #
8277103
Study Section
Special Emphasis Panel (ZRG1-CVRS-C (02))
Program Officer
Wong, Renee P
Project Start
2010-07-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$744,873
Indirect Cost
$261,189
Name
University of California Los Angeles
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Akaike, Toru; Du, Na; Lu, Gang et al. (2017) A Sarcoplasmic Reticulum Localized Protein Phosphatase Regulates Phospholamban Phosphorylation and Promotes Ischemia Reperfusion Injury in the Heart. JACC Basic Transl Sci 2:160-180
Rose, Beth A; Yokota, Tomohiro; Chintalgattu, Vishnu et al. (2017) Cardiac myocyte p38? kinase regulates angiogenesis via myocyte-endothelial cell cross-talk during stress-induced remodeling in the heart. J Biol Chem 292:12787-12800
Dong, Weibing; Zhou, Meiyi; Dong, Mei et al. (2016) Keto acid metabolites of branched-chain amino acids inhibit oxidative stress-induced necrosis and attenuate myocardial ischemia-reperfusion injury. J Mol Cell Cardiol 101:90-98
Sun, Haipeng; Olson, Kristine C; Gao, Chen et al. (2016) Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 133:2038-49
Gao, Chen; Wang, Yibin (2016) Positive Role for a Negative Calcineurin Regulator in Cardiac Hypertrophy. Hypertension 67:841-2
Sun, Haipeng; Wang, Yibin (2015) The elusive philosopher's stone in young blood. Circ Res 117:906-8
Sun, Haipeng; Gao, Chen; Wang, Yibin (2015) A H(a)rd Way to Adapt in Cardiac Hypertrophy. Circ Res 117:484-6
Pan, Bang-fen; Gao, Chen; Ren, Shu-xun et al. (2015) Regulation of PP2Cm expression by miRNA-204/211 and miRNA-22 in mouse and human cells. Acta Pharmacol Sin 36:1480-6
Lau, Edward; Huang, Derrick; Cao, Quan et al. (2015) Spatial and temporal dynamics of the cardiac mitochondrial proteome. Expert Rev Proteomics 12:133-46
Sun, Haipeng; Wang, Yibin (2014) Interferon regulatory factors in heart: stress response beyond inflammation. Hypertension 63:663-4

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