The objective of this study is to investigate the role and molecular mechanisms of tissue kallikrein in cardiac protection after myocardial infarction in normal and genetically modified animals. Our recent studies have shown that tissue kallikrein gene or protein delivery protects against organ damage in the heart, kidney and brain through anti- oxidative, anti-apoptotic, anti-inflammatory and angiogenic effects. These results indicate that kallikrein is a pleiotropic agent ideal for combined gene and stem cell therapies for cardiovascular diseases. Therefore, we hypothesize that tissue kallikrein gene delivery or kallikrein modified-mesenchymal stem cell (TK-MSC) implantation provides superior benefits in cardiac repair by inhibiting apoptosis and promoting neovascularization and cardiomyocyte regeneration. We intend to fulfill the following specific aims: 1) determine the effect and signaling mechanisms of tissue kallikrein on angiogenesis, arteriogenesis and ventricular remodeling in rats after myocardial infarction, and on migration, growth and capillary tube formation in endothelial cells;2) determine whether tissue kallikrein directly activates kinin B2 receptors via proteolysis, independent of kinin formation, to prevent cardiomyocyte apoptosis and inflammation and cardiac dysfunction in kininogen- deficient rats after acute myocardial infarction;3) determine the viability and effects of TK-MSCs on cardiac function as well as their paracrine effects on cardiomyocyte apoptosis and inflammation in rats after acute myocardial infarction;4) determine the effects of graft TK-MSCs on cardiac repair and remodeling by promoting neovascularization and cardiac regeneration in rats with post-infarction heart failure. Our long-term goal is to develop a novel therapeutic strategy for myocardial repair and regeneration of damaged myocardium using kallikrein gene and cell-based therapies. This study should generate new and important information to provide the impetus for developing therapeutic regimens in the prevention of heart failure. Project Narrative: Our objective is to investigate the molecular mechanisms of tissue kallikrein in cardiac protection in animal models with acute and chronic myocardial infarction. Our long-term goal is to develop a novel therapeutic strategy for myocardial repair and regeneration of damaged myocardium using kallikrein gene- and cell-based therapies. This study should generate important information to provide the impetus for developing therapeutic regimens in the prevention of cardiac dysfunction and heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL029397-29
Application #
8281655
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Gao, Yunling
Project Start
1986-07-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
29
Fiscal Year
2012
Total Cost
$365,063
Indirect Cost
$117,563
Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Chao, Julie; Bledsoe, Grant; Chao, Lee (2014) Tissue kallikrein-kinin therapy in hypertension and organ damage. Prog Drug Res 69:37-57
Li, Pengfei; Bledsoe, Grant; Yang, Zhi-Rong et al. (2014) Human kallistatin administration reduces organ injury and improves survival in a mouse model of polymicrobial sepsis. Immunology 142:216-26
Gao, Lin; Li, Pengfei; Zhang, Jingmei et al. (2014) Novel role of kallistatin in vascular repair by promoting mobility, viability, and function of endothelial progenitor cells. J Am Heart Assoc 3:e001194
Zhang, Jingmei; Yang, Zhirong; Li, Pengfei et al. (2013) Kallistatin antagonizes Wnt/*-catenin signaling and cancer cell motility via binding to low-density lipoprotein receptor-related protein 6. Mol Cell Biochem 379:295-301
Yao, Yuyu; Sheng, Zulong; Li, YeFei et al. (2013) Tissue kallikrein-modified human endothelial progenitor cell implantation improves cardiac function via enhanced activation of akt and increased angiogenesis. Lab Invest 93:577-91
Gao, Lin; Bledsoe, Grant; Yin, Hang et al. (2013) Tissue kallikrein-modified mesenchymal stem cells provide enhanced protection against ischemic cardiac injury after myocardial infarction. Circ J 77:2134-44
Gao, Lin; Chao, Lee; Chao, Julie (2010) A novel signaling pathway of tissue kallikrein in promoting keratinocyte migration: activation of proteinase-activated receptor 1 and epidermal growth factor receptor. Exp Cell Res 316:376-89
Yin, Hang; Gao, Lin; Shen, Bo et al. (2010) Kallistatin inhibits vascular inflammation by antagonizing tumor necrosis factor-alpha-induced nuclear factor kappaB activation. Hypertension 56:260-7
Shen, Bo; Chao, Lee; Chao, Julie (2010) Pivotal role of JNK-dependent FOXO1 activation in downregulation of kallistatin expression by oxidative stress. Am J Physiol Heart Circ Physiol 298:H1048-54
Chao, Julie; Shen, Bo; Gao, Lin et al. (2010) Tissue kallikrein in cardiovascular, cerebrovascular and renal diseases and skin wound healing. Biol Chem 391:345-55

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