The objective of this application is to investigate the role of kallistatin in protection against cardiac injury induced by hypertension and ischemic heart disease. Kallistatin was discovered, purified and cloned in our laboratory as a specific tissue kallikrein-binding protein and a unique serine proteinase inhibitor. Purified kallistatin is a potent new vasodilator as it directly induces vasorelaxation and reduces blood pressure independent of its kallikrein inhibitory activity. Transgenic mice overexpressing kallistatin are hypotensive, and kallistatin gene delivery in hypertensive rats causes a prolonged reduction of blood pressure. Furthermore, circulating kallistatin levels are markedly reduced in animal models of hypertension, cardiac and renal dysfunction associated with increased inflammation and oxidative stress. These findings suggest a potential role of kallistatin in inflammation-related hypertension and cardiovascular disease. Our recent studies showed that kallistatin gene transfer reduced inflammatory cytokines and joint swelling in collagen-induced arthritis, and reduced inflammatory cell infiltration and apoptosis in the ischemic heart after ischemia/reperfusion (I/R). Based on these new findings, we hypothesize that kallistatin protects against hypertension and ischemic heart disease by inhibiting oxidative stress, inflammation and cardiomyocyte apoptosis. In order to test this hypothesis, we will pursue the following specific aims: 1) to determine the structural elements of kallistatin required for inhibiting inflammation and cardiomyocyte apoptosis after myocardial I/R, 2) to determine the signaling pathways mediated by kallistatin in inhibiting inflammation after myocardial I/R, 3) to determine the signaling pathways mediated by kallistatin in inhibiting apoptosis after myocardial I/R, and 4) to determine the protective role of endogenous kallistatin in hypertension and ischemic heart disease using kallistatin knockout mice and kallistatin knockdown rats by RNA interference. This research proposal should provide significant insights into the role and regulatory mechanisms of kallistatin in the cardiovascular system, and foster the development of therapeutic agents for halting inflammation-related hypertension and ischemic heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL044083-15
Application #
6926772
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Lin, Michael
Project Start
1990-02-01
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
15
Fiscal Year
2005
Total Cost
$292,000
Indirect Cost
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 (2016) Protective Role of Kallistatin in Vascular and Organ Injury. Hypertension 68:533-41
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
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
Zhu, Haidong; Chao, Julie; Kotak, Ishita et al. (2013) Plasma kallistatin is associated with adiposity and cardiometabolic risk in apparently healthy African American adolescents. Metabolism 62:642-6
Liu, Yuying; Bledsoe, Grant; Hagiwara, Makato et al. (2012) Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling. Am J Physiol Renal Physiol 303:F1230-8
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
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; Gao, Lin; Hsu, Yi-Te et al. (2010) Kallistatin attenuates endothelial apoptosis through inhibition of oxidative stress and activation of Akt-eNOS signaling. Am J Physiol Heart Circ Physiol 299:H1419-27

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