Gene expression is regulated at multiple levels including the cap-dependent translation of mRNA into proteins. Eukaryotic translation initiation factor4E (eIF4E) binds to the 5'-m7GTP cappresent on all eukaryotic cytoplasmic mRNAs. eIF4E is the central component of the cap-dependent translation initiation complex (eIF4F). The assembly of eIF4F is negatively regulated by 4E-binding proteins (4E-BPs or BPs), which bind eIF4E and block eIF4F assembly to inhibit cap-dependent translation. Three BPs have been identified as BP1, BP2 and BP3 (BP3). We have found that LV BP1 protein expression is greatly increased in advanced congestive heart failure (CHF). We examined the effect of double gene knockout (DKO) of BP1 and BP2 on transverse aortic constriction (TAC) or myocardial infarct induced CHF in mice, and the results demonstrated that BP1/2 DKO profoundly improved the survival rate and LV function in these mice. We also found that BP1/2 DKO increased LV sarcoplasmic reticulum Ca++ ATPase (SERCA2a) protein content ~2.5 fold at the protein level. Based on these preliminary data, the overall goal of this proposal is to determine how enhancing cap-dependent translation initiation by BP1/2 DKO and BP1 KO exert their profound cardiac protective effect against the development of CHF in mice by achieving following research objectives: (i) Determine the consequences of enhancing cap-dependent translational initiation by DKO on stress-induced CHF. Our working hypothesis is that enhancing cap-dependent translation initiation by DKO will protect the heart from TAC or infarct induced CHF;(ii) Identify whether the cardioprotective effect observed in DKO mice is mainly due to loss of function of BP1 or BP2. Our working hypothesis is that the cardiac protective effect is mainly due to the deletion of BP1, and that cardiac myocyte specific BP1 overexpression will cause or exacerbates LV dysfunction;(iii) Identify underlying molecular mechanisms for the cardioprotective effect of enhancing translational initiation by BP1/2 DKO. Our working hypothesis is that BP1/2 DKO will improve the translational efficiency of mRNAs (such as SERCA2a) that have an excessive amount of secondary structure in the 5'-untranslatedregions (5'-UTRs). The project will take advantage of mouse models with targeted disruption of BP1, BP2 and BP1/2, cardiac specific BP1 transgenic mice and of technologies for combined analysis of the transcriptome and translatome. Our research team includes experts in translational control (Dr. Bitterman), molecular cardiology and experimental CHF models (Dr. Chen), polyribosome microarrays (Dr. Bitterman), and membrane protein complexes involved in calcium transport (such as SERCA2a) in cardiac myocytes (Dr. David Thomas). These studies will provide novel insights into the role of cap-dependent translation initiation on the development of CHF. Our preliminary finding indicates that regulation of cap-dependent translation initiation by targeting 4E-binding proteins may be a novel therapeutic approach to treat CHF.

Public Health Relevance

Cardiovascular disease ranks as America's No. 1 killer that accounts for nearly one million deaths each year. 4E binding proteins (4E-BPs) play an important role in regulating the translation of mRNA into proteins. We recently found that 4E-BP1 was significantly increased in the advance heart failure. The purpose of this project is to determine the effect 4E-BP gene deletion on the development of congestive heart failure and to understand how 4E-BPs play a critical role in regulating the development of congestive heart failure. The findings from this project are going to advance our understanding of the development of heart failure and to identify novel new therapeutic targets for treating congestive heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105406-04
Application #
8666798
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2011-08-05
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$369,950
Indirect Cost
$124,950
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Bache, Robert J; Chen, Yingjie (2014) NOX2-induced myocardial fibrosis and diastolic dysfunction: role of the endothelium. J Am Coll Cardiol 63:2742-4
Liu, Xiaoyu; Kwak, Dongmin; Lu, Zhongbing et al. (2014) Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling. Hypertension 64:738-44
Liu, Yi; Jiang, Xiao-Li; Liu, Yu et al. (2014) Toll-interacting protein (Tollip) negatively regulates pressure overload-induced ventricular hypertrophy in mice. Cardiovasc Res 101:87-96
Wang, Huan; Xu, Xin; Fassett, John et al. (2014) Double-stranded RNA-dependent protein kinase deficiency protects the heart from systolic overload-induced congestive heart failure. Circulation 129:1397-406
Jiang, Ding-Sheng; Liu, Yu; Zhou, Heng et al. (2014) Interferon regulatory factor 7 functions as a novel negative regulator of pathological cardiac hypertrophy. Hypertension 63:713-22
Chen, Yingjie; Zhang, Ping; Li, Jingxin et al. (2014) Inducible nitric oxide synthase inhibits oxygen consumption in collateral-dependent myocardium. Am J Physiol Heart Circ Physiol 306:H356-62
Xu, Xin; Lu, Zhongbing; Fassett, John et al. (2014) Metformin protects against systolic overload-induced heart failure independent of AMP-activated protein kinase ?2. Hypertension 63:723-8
Lu, Zhongbing; Xu, Xin; Fassett, John et al. (2014) Loss of the eukaryotic initiation factor 2* kinase general control nonderepressible 2 protects mice from pressure overload-induced congestive heart failure without affecting ventricular hypertrophy. Hypertension 63:128-35
Fassett, John T; Hu, Xinli; Xu, Xin et al. (2013) AMPK attenuates microtubule proliferation in cardiac hypertrophy. Am J Physiol Heart Circ Physiol 304:H749-58
Lu, Jing; Bian, Zhou-Yan; Zhang, Ran et al. (2013) Interferon regulatory factor 3 is a negative regulator of pathological cardiac hypertrophy. Basic Res Cardiol 108:326

Showing the most recent 10 out of 16 publications