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Grant Abstract

Grant Number: 1R21AT003255-01A2
Project Title: Herbal Effects on Oxidant Dynamics in Cardiomyocytes

Abstract: DESCRIPTION (provided by applicant): Acute and chronic heart diseases, which cause significant morbidity and mortality, have often been treated by herbal medications in traditional medicinal systems. Since reactive oxygen species (ROS) mediate pathogenesis of heart disease, studying the role of antioxidant herbs in prevention or attenuation of heart disease and the involved mechanisms is extremely important. We propose to investigate two commonly used herbs with antioxidant properties, namely grape seed proanthocyanidin extract (GSPE) and Scutellaria baicalensis extract (SbE), which are potent ROS scavengers. In the current proposal, we plan to evaluate whether long-term pretreatment with the extracts can induce antioxidant protection. Our preliminary results in chick cardiomyocytes pretreated with either GSPE or SbE or extract fractions or some active constituents for 48-72 hr demonstrate significant protection against both an endogenous and exogenous oxidant onslaught. The findings suggest that indirect effects of herbal pretreatment reduce intracellular ROS activity, which would be of benefit in cardiac disease. This is possibly achieved by herbal metabolites within the cell that scavenge ROS and by altered gene expression with synthesis of proteins that modulate ROS activity. We hypothesize that pretreatment of cardiomyocytes with GSPE or SbE results in significant attenuation of ROS-induced injury and alteration in ROS-dependent processes mediated through upregulation of cellular antioxidant capacity. The proposed experiments will be evaluated in a neonatal mouse cardiomyocyte model pretreated with the test herbs for 1-5 days. The specific aims are to investigate whether pretreatment with GSPE or SbE attenuate oxidant injury in the cardiomyocytes during simulated oxidant stress, whether herbal pretreatment modulates cellular responses to stimuli that mediate actions through ROS, and whether the altered responses can be partly explained by upregulated gene expression of antioxidant proteins. We will also evaluate whether the upregulation of antioxidant activity can be attributed to specific bioactive fractions and constituents of the extracts. Results will subsequently be confirmed with the use of "knockout extracts" in which the active constituents are removed from their original matrix. The proposed study will highlight the role of GSPE and SbE in altering the outcome of ROS-dependent activity within cardiomyocytes. Our results could demonstrate that these herbs have a potential in the prevention and treatment of cardiac disease. The proposed study will highlight the role of GSPE and SbE in altering the outcome of ROS-dependent cellular events. Our results could demonstrate a significant potential of the herbs in the prevention and treatment of cardiac disease.

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