This proposal builds upon work suggesting that the herbal extract Scutellaria baicalensis (SbE) and its major component baicalein may simulate many important components of cardiac preconditioning (PC), i.e. trigger transient mitochondrial oxidant signaling, activate the survival kinase Akt, attenuate reperfusion reactive oxygen species (ROS) and increase reperfusion nitric oxide (NO) generation. It is one of the few PC compounds we have tested that provides significant protection in 3 lethal models of cardiac ischemia/ reperfusion (I/R): chick cardiomyocytes, murine cardiomyocytes and murine cardiac arrest. An herbal extract already used in popular alternative medicine has practical advantages for use as a pharmacologic cardiac PC agent in patients at risk for adverse cardiac events. This proposal seeks to further examine PC protection induced by SbE and/or baicalein in murine cardiomyocytes by determining the mechanisms involved in generating the protective phenotype. We hypothesize that SbE and/or baicalein will induce PC protection against murine cardiomyocyte I/R injury via a transient ROS generation that initiates the activation of PKCe and/or Akt resulting in eNOS activation and increased reperfusion NO generation. Specifically, Aim 1 will optimize the dose of SbE and/or baicalein that trigger ROS-mediated PC, and determine the source and importance of these ROS using various antioxidants and mitochondrial inhibitors. Further, we will test whether these transient ROS induce augmented reperfusion NO and protection against apoptosis.
In Aim 2, we will evaluate the pathway by which the most effective herb-induced PC protocol confers protection. We will assess the activation of PKCe and/or Akt in herb-induced PC using PKCe translocation, Akt phosphorylation, and Akt activity. We also will examine the role of ROS in inducing PKCe and/or Akt activation and the effect of this kinase activation on eNOS phosphorylation and NO generation using kinase inhibitors, siRNA gene silencing and knockout strategies for eNOS and Akt-1. These results will help clarify important PC pathways in murine cardiomyocytes, focusing on how mitochondrial oxidants, certain stress kinases, and eNOS may interact to protect against I/R injury. This work will be used to plan translational studies of herb-PC into our mouse model of cardiac arrest. Finally, a better understanding of SbE- and/or baicalein PC could lead to new oxidant-mediated PC clinical therapies.

Public Health Relevance

From a layperson perspective, there are few medicines that protect against future heart attacks. In addition, many studies of herb compounds as alternative medicines have focused on their antioxidant effects. This proposal will study an herb mixture that actually increases a type of oxidant stress in the heart that may help condition it and protect against future heart attack injury.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AT003441-02
Application #
7841950
Study Section
Special Emphasis Panel (ZAT1-DB (28))
Program Officer
Weber, Wendy J
Project Start
2009-05-01
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$161,393
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Li, Jing; Fettiplace, Michael; Chen, Sy-Jou et al. (2014) Lipid emulsion rapidly restores contractility in stunned mouse cardiomyocytes: a comparison with therapeutic hypothermia. Crit Care Med 42:e734-40
Chang, Wei-Tien; Li, Jing; Vanden Hoek, Matthew S et al. (2013) Baicalein preconditioning protects cardiomyocytes from ischemia-reperfusion injury via mitochondrial oxidant signaling. Am J Chin Med 41:315-31
Li, Jing; Shao, Zuo-Hui; Xie, Jing-Tian et al. (2012) The effects of ginsenoside Rb1 on JNK in oxidative injury in cardiomyocytes. Arch Pharm Res 35:1259-67
Qi, Lian-Wen; Wang, Chong-Zhi; Yuan, Chun-Su (2011) Ginsenosides from American ginseng: chemical and pharmacological diversity. Phytochemistry 72:689-99
Chang, Wei-Tien; Li, Jing; Haung, Hsien-Hao et al. (2011) Baicalein protects against doxorubicin-induced cardiotoxicity by attenuation of mitochondrial oxidant injury and JNK activation. J Cell Biochem 112:2873-81
Shao, Zuo-Hui; Sharp, Willard W; Wojcik, Kimberly R et al. (2010) Therapeutic hypothermia cardioprotection via Akt- and nitric oxide-mediated attenuation of mitochondrial oxidants. Am J Physiol Heart Circ Physiol 298:H2164-73
Li, Xiao-Li; Sun, Shi; Du, Guang-Jian et al. (2010) Effects of Oplopanax horridus on human colorectal cancer cells. Anticancer Res 30:295-302
Li, Jing; Liu, Huiping; Ramachandran, Srinivasan et al. (2010) Grape seed proanthocyanidins ameliorate Doxorubicin-induced cardiotoxicity. Am J Chin Med 38:569-84
Wang, Chong-Zhi; Aung, Han H; Mehendale, Sangeeta R et al. (2010) High performance liquid chromatographic analysis and anticancer potential of Oplopanax horridus: comparison of stem and berry extracts. Fitoterapia 81:132-9
Wang, Chong-Zhi; Li, Xiao-Li; Wang, Qian-Fei et al. (2010) Selective fraction of Scutellaria baicalensis and its chemopreventive effects on MCF-7 human breast cancer cells. Phytomedicine 17:63-8

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