The inner layers of the left ventricular wall (ENDO) are known to be the most susceptible to oxidative stresses. We hypothesize that there is transmural gradient of reserves of ATP production rate via both creatine kinase (CK) and ATPase, which is the lowest in ENDO that results in the ENDO vulnerability in LVH hearts. Despite the intense interest in cellular therapy for myocardial repair, the majority of research reports to date have been designed to repair or prevent LV dysfunction in hearts with myocardial infarction secondary to coronary arteries diseases. Given the fact that more than 50% of heart transplant CHF patients whose etiology is nonischemic, studies using nonischemic large animal model is urgently needed before pursuing large scale clinical trials. The mechanisms underlying the beneficial effects of cellular therapy are not well defined. It is a consistent finding that the engraftment rate is low. However, the long term improvement of the LV contractile function of the recipient heart is consistently observed. Therefore, in addition to the myocardial regeneration from the engrafted cells the improved LV chamber function is also likely related to the changes of the recipient myocardial protein deferential expression. Comparing two swine models of LVH secondary to pressure overload or to postinfarction LV remodeling, the effects of MSCs transplantation on LV contractile function (MRI);myocardial perfusion, myocardial oxygenation level (1H-MRS);and ATP turnover rate (31P- MRS) will be measured biweekly for 8 weeks, the recipient myocardial differential protein expression will be examined by comparative proteomics.
The specific aims are: SA1. Using the recently developed T1-nom P-31 magnetization saturation transfer (MST) methods to examine whether the myocardial ATP turnover rate via CK and ATPase are most severely altered in the ENDO of LVH hearts, and whether the severity of which is linearly related to the severity of the LV dysfunction. SA2. To examine whether the functional beneficial effects of allogenic MSC transplantation are accompanied by the improvement of ATP production capacity via CK and ATPase in the ENDO of LVH hearts with or without ischemic coronary artery diseases, and whether these functional benefits are accompanied by regeneration of myocardium from both engrafted MSCs as well as endogenous CPCs. SA3: To examine whether the functional beneficial effects of cellular therapy are associated with the differential protein expression profle of the recipient myocardium. We will employ cutting edge liquid chromatography mass spectrometry-based comparative proteomics method to quantitatively determine the changes in the protein expression with a special emphasis on growth factors family proteins and proteins involved in energy metabolism. The findings of the experiments will elucidate for the first time, the transmural gradient of ATP turnover rate via both CK and ATPase in the in vivo LVH hearts. The findings of these studies will advance our understanding of the mechanisms of cellular therapy in myocardial repair, and lead to better diagnostic and therapeutic modalities for CHF patients.

Public Health Relevance

The inner layers of the left ventricular wall (ENDO) are the most susceptible to oxidative stresses. Using our recently established NMR methods, this set of experiments will for the first time, examine whether the ENDO lower ATP production capacity via creatine kinase (CK) and ATPase results in the ENDO vulnerability in LVH hearts. Using swine models of LVH secondary to pressure overload or post-infarction LV remodeling as well as the quantitative proteomics method, these studies will also examine whether the functional beneficial effects of the cell transplantation are associated with the improvement of ATP production capacity via both CK and ATPase, which are accompanied by the changes in the protein expression profile of the recipient myocardium particularly the growth factors family proteins and proteins involved in energy metabolism. The findings of the experiments will elucidate for the first time, the transmural gradient of ATP turnover rate via CK and ATPase in the in vivo LVH hearts with or without stem cell transplantation;and will advance our understanding of the mechanisms of cellular therapy in myocardial repair that lead to better diagnostic and therapeutic modalities for CHF patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL114120-01A1
Application #
8385977
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wong, Renee P
Project Start
2012-08-10
Project End
2016-05-31
Budget Start
2012-08-10
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$667,215
Indirect Cost
$199,207
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
Zhu, Wuqiang; Gao, Ling; Zhang, Jianyi (2017) Pluripotent Stem Cell Derived Cardiac Cells for Myocardial Repair. J Vis Exp :
Yang, Libang; Gregorich, Zachery R; Cai, Wenxuan et al. (2017) Quantitative Proteomics and Immunohistochemistry Reveal Insights into Cellular and Molecular Processes in the Infarct Border Zone One Month after Myocardial Infarction. J Proteome Res 16:2101-2112
Borovjagin, Anton V; Ogle, Brenda M; Berry, Joel L et al. (2017) From Microscale Devices to 3D Printing: Advances in Fabrication of 3D Cardiovascular Tissues. Circ Res 120:150-165
Yang, Libang; Gao, Ling; Nickel, Thomas et al. (2017) Lactate Promotes Synthetic Phenotype in Vascular Smooth Muscle Cells. Circ Res 121:1251-1262
Gao, Ling; Kupfer, Molly E; Jung, Jangwook P et al. (2017) Myocardial Tissue Engineering With Cells Derived From Human-Induced Pluripotent Stem Cells and a Native-Like, High-Resolution, 3-Dimensionally Printed Scaffold. Circ Res 120:1318-1325
Yang, Libang; Geng, Zhaohui; Nickel, Thomas et al. (2016) Differentiation of Human Induced-Pluripotent Stem Cells into Smooth-Muscle Cells: Two Novel Protocols. PLoS One 11:e0147155
Jang, Albert; Xiong, Qiang; Zhang, Pengyuan et al. (2016) Transmurally differentiated measurement of ATP hydrolysis rates in the in vivo porcine hearts. Magn Reson Med 75:1859-66
Jameel, Mohammad N; Xiong, Qiang; Mansoor, Abdul et al. (2016) ATP sensitive K(+) channels are critical for maintaining myocardial perfusion and high energy phosphates in the failing heart. J Mol Cell Cardiol 92:116-21
Xiong, Qiang; Zhang, Pengyuan; Guo, Jing et al. (2015) Myocardial ATP hydrolysis rates in vivo: a porcine model of pressure overload-induced hypertrophy. Am J Physiol Heart Circ Physiol 309:H450-8
Cui, Weina; Jang, Albert; Zhang, Pengyuan et al. (2015) Early Detection of Myocardial Bioenergetic Deficits: A 9.4 Tesla Complete Non Invasive 31P MR Spectroscopy Study in Mice with Muscular Dystrophy. PLoS One 10:e0135000

Showing the most recent 10 out of 25 publications