Heart disease is the leading cause of death in the United States. Heart transplantation is the only clinically effective therapy for end-stage heart failure, but it is available to only a few patients. Transplantation of immature cells, such as stem cells or myoblasts, in the infarct area of the heart, known as cell therapy, appears to be a promising alternative strategy. The myoblasts, derived from leg skeletal muscle tissue, can proliferate and differentiate into functional cells and thereby improve heart function. However, the probability of survival/proliferation of the transplanted myoblasts is often less than 1%. Severe hypoxia (low oxygen levels) is hypothesized as a factor responsible for the poor outcome of cell therapy. Thus, there is a pressing need to precisely evaluate the oxygen concentration, particularly intracellular oxygenation, in the transplanted myoblasts as a function of cardiac tissue regeneration. Therefore, the goal of the present study is to develop innovative probes and methods for noninvasive monitoring of the changes in the cellular oxygenation during myocardial regeneration. We have developed a new class of spin probes that can be directly detected by electron paramagnetic resonance (EPR) spectroscopy/imaging with markedly higher sensitivity for detection. The probes are composed of stacks of neutral radicals of lithiated naphthalocyanine macrocyclic ligands. In addition, the probes can report absolute values of tissue oxygen concentration with remarkable oxygen sensitivity (better than 0.1 Torr). They enable precise, accurate and repeated measurements of myocardial oxygenation over a period of several months in closed chests. The probes can be efficiently internalized into cells to study cell proliferation and migration. The objective of this proposal is to utilize these novel probes for noninvasive monitoring of the survival and proliferation of the transplanted cells in the infarct area of the myocardium. The proposal specifically seeks to study: 1. Establishment of optimal internalization procedures and characterization of the spin probe in myoblasts for cell-tracking and determination of intracellular oxygen concentration;2. Noninvasive monitoring of in situ oxygenation at the site of implant, migration, and engraftment of transplanted stem cells in infarcted hearts;3. Evaluation of the efficacy of myoblast stem cells subjected to hypoxic culture or intermittent hypoxia/reoxygenation on the survival, retention, integration, and in situ oxygenation after their transplantation in the infarcted heart. The availability of these innovative probes and technologies will enhance our ability to monitor cell therapy and should open new avenues in the treatment of heart disease in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB006153-03
Application #
7619896
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Liu, Guoying
Project Start
2007-07-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
3
Fiscal Year
2009
Total Cost
$335,915
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Ravi, Yazhini; Selvendiran, Karuppaiyah; Naidu, Shan K et al. (2013) Pulmonary hypertension secondary to left-heart failure involves peroxynitrite-induced downregulation of PTEN in the lung. Hypertension 61:593-601
Khan, Mahmood; Brauner, Mark E; Plewa, Michael C et al. (2013) Effect of pulmonary-generated reactive oxygen species on left-ventricular dysfunction associated with cardio-pulmonary ischemia-reperfusion injury. Cell Biochem Biophys 67:275-80
Saini, Uksha; Gumina, Richard J; Wolfe, Brian et al. (2013) Preconditioning mesenchymal stem cells with caspase inhibition and hyperoxia prior to hypoxia exposure increases cell proliferation. J Cell Biochem 114:2612-23
Khan, Mahmood; Meduru, Sarath; Gogna, Rajan et al. (2012) Oxygen cycling in conjunction with stem cell transplantation induces NOS3 expression leading to attenuation of fibrosis and improved cardiac function. Cardiovasc Res 93:89-99
Hassan, Fatemat; Meduru, Sarath; Taguchi, Kazuaki et al. (2012) Carvedilol enhances mesenchymal stem cell therapy for myocardial infarction via inhibition of caspase-3 expression. J Pharmacol Exp Ther 343:62-71
Dayton, Alex; Selvendiran, Karuppaiyah; Meduru, Sarath et al. (2011) Amelioration of doxorubicin-induced cardiotoxicity by an anticancer-antioxidant dual-function compound, HO-3867. J Pharmacol Exp Ther 339:350-7
Khan, Mahmood; Meduru, Sarath; Pandian, Ramasamy P et al. (2011) Effect of oxygenation on stem-cell therapy for myocardial infarction. Adv Exp Med Biol 701:175-81
Chacko, Simi M; Ahmed, Shabnam; Selvendiran, Karuppaiyah et al. (2010) Hypoxic preconditioning induces the expression of prosurvival and proangiogenic markers in mesenchymal stem cells. Am J Physiol Cell Physiol 299:C1562-70
Bognár, Balázs; Ahmed, Shabnam; Kuppusamy, M Lakshmi et al. (2010) Synthesis and study of new paramagnetic and diamagnetic verapamil derivatives. Bioorg Med Chem 18:2954-63
Khan, Mahmood; Meduru, Sarath; Mostafa, Mahmoud et al. (2010) Trimetazidine, administered at the onset of reperfusion, ameliorates myocardial dysfunction and injury by activation of p38 mitogen-activated protein kinase and Akt signaling. J Pharmacol Exp Ther 333:421-9

Showing the most recent 10 out of 21 publications