Abstract

Heart failure is one of the most important diseases in the US and the world. Loss of contractility and blunted response to adrenergic stimulation are common pathophysiological features of a failing heart. Cardiac SR calcium cycling is a highly regulated process and its abnormalities play a major role in heart failure. Recently, our laboratory has identified a novel isoform of protein phosphatase 2C (PP2Ce) which has the following interesting features. PP2Ce is highly expressed in heart and the protein is targeted specifically on SR membrane of cardiomyocytes. PP2Ce has specific activity towards p-PLN without significant impact on p-RyR2. PP2Ce protein has a rapid turn- over rate and its expression is significantly induced by prolonged 2AR stimulation at post-transcriptional level. PP2Ce expression suppresses 2AR mediated induction in calcium transients and contractility, and promotes failure following ischemia/reperfusion injury. PP2Ce inactivation sustains 2AR induced contractility, protects against I/R injury and attenuates pressure-overload induced hypertrophy and heart failure. These findings lead to our exciting new hypothesis that PP2Ce is a novel phosphatase of PLN with a significant contribution to 2AR signaling and functional regulation in stressed hearts. In this proposal, we aim to uncover the regulatory mechanisms of PP2Ce expression and the functional significance of PP2Ce mediated signaling. Specifically, we plan to accomplish the following three aims:
Specific aim 1 : To investigate the molecular basis and cellular impact of PP2Ce-mediated PLN dephosphorylation. We will determine the interaction between PP2Ce and PLN, and the impact of PP2Ce expression/inactivation on SR calcium homeostasis.
Specific aim 2 : To investigate the regulatory mechanism of PP2Ce expression. We will dissect the contributing factors in PP2Ce protein expression, PLN targeting and 2AR mediated regulation of its turn-over.
Specific aim 3 : To determine the functional role of PP2Ce activity in intact heart. We will determine the functional impact of PP2Ce expression and inactivation in response to I/R injury and pressure-overload. In addition, we will determine functional significance of PLN in PP2Ce mediated cardiac protection and pathological remodeling.

Public Health Relevance

Cardiac SR calcium regulation and dysfunction is critically important to cardiomyocyte contractility under basal and diseased conditions. Investigation of a novel phosphatase for PLN, a key regulator of SR calcium cycling can bring new insights to the regulatory network in this process and helps to explore new avenues of therapy for heart failure.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL108186-05
Application #
8784234
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2011-04-01
Project End
2015-12-31
Budget Start
2015-01-01
Budget End
2015-12-31
Support Year
5
Fiscal Year
2015
Total Cost
$346,500
Indirect Cost
$121,500

  Institution

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

  Publications

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
Touma, Marlin; Kang, Xuedong; Gao, Fuying et al. (2017) Wnt11 regulates cardiac chamber development and disease during perinatal maturation. JCI Insight 2:
Shimizu, Hirohito; Langenbacher, Adam D; Huang, Jie et al. (2017) The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes. Elife 6:
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
Gao, Chen; Ren, Shuxun; Lee, Jae-Hyung et al. (2016) RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure. J Clin Invest 126:195-206
Yokota, Tomohiro; Wang, Yibin (2016) p38 MAP kinases in the heart. Gene 575:369-376
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
Touma, Marlin; Kang, Xuedong; Zhao, Yan et al. (2016) Decoding the Long Noncoding RNA During Cardiac Maturation: A Roadmap for Functional Discovery. Circ Cardiovasc Genet 9:395-407
Wang, Zhihua; Zhang, Xiao-Jing; Ji, Yan-Xiao et al. (2016) The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat Med 22:1131-1139

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