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)
Type
Research Project (R01)
Project #
5R01HL114120-03
Application #
8676931
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wong, Renee P
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Zhang, Liying; Guo, Jing; Zhang, Pengyuan et al. (2015) Derivation and high engraftment of patient-specific cardiomyocyte sheet using induced pluripotent stem cells generated from adult cardiac fibroblast. Circ Heart Fail 8:156-66
Zhang, Sophia; Dutton, James R; Su, Liping et al. (2014) The influence of a spatiotemporal 3D environment on endothelial cell differentiation of human induced pluripotent stem cells. Biomaterials 35:3786-93
Ablorh, Naa-Adjeley D; Dong, Xiaoqiong; James, Zachary M et al. (2014) Synthetic phosphopeptides enable quantitation of the content and function of the four phosphorylation states of phospholamban in cardiac muscle. J Biol Chem 289:29397-405
Jameel, Mohammad Nurulqadr; Hu, Qingsong; Zhang, Jianyi (2014) Myocytes oxygenation and high energy phosphate levels during hypoxia. PLoS One 9:e101317
Wendel, Jacqueline S; Ye, Lei; Zhang, Pengyuan et al. (2014) Functional consequences of a tissue-engineered myocardial patch for cardiac repair in a rat infarct model. Tissue Eng Part A 20:1325-35
Ye, Lei; Zimmermann, Wolfram-Hubertus; Garry, Daniel J et al. (2013) Patching the heart: cardiac repair from within and outside. Circ Res 113:922-32
Ye, Lei; Zhang, Sophia; Greder, Lucas et al. (2013) Effective cardiac myocyte differentiation of human induced pluripotent stem cells requires VEGF. PLoS One 8:e53764
Ye, Lei; Zhang, Pengyuan; Duval, Sue et al. (2013) Thymosin *4 increases the potency of transplanted mesenchymal stem cells for myocardial repair. Circulation 128:S32-41
Zhang, Jianyi Jay (2013) Mechanisms of cell therapy for clinical investigations: an urgent need for large-animal models. Circulation 128:92-4