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"REDOX REGULATION OF 5-AMP-ACTIVATED PROTEIN KINASE BY THIOREDOXIN-1 IN THE HEART"

by
Dan Shao
Cell Biology and Molecular Medicine Program
B.S. 2005, Wuhan University, China


Thesis Advisor: Junichi Sadoshima, M.D., Ph.D.
Professor
Department of Cell Biology and Molecular Medicine

Wednesday, May 16, 2012
3:00 P.M., MSB Room G-609


Abstract

Thioredoxin1 (Trx1) is a 12KD anti-oxidant that plays a key role in maintaining the reducing environment in cells. Trx1 also exerts its biological function through direct and specific protein-protein interaction with signaling molecules. Using Trx1 C35S (Cysteine 35 to Serine) trapped mutant, we successfully identify that 5-AMP-activated protein kinase (AMPK) is an important substrate that mediates Trx1 cardioprotective effect in the heart. AMPK is an essential metabolic regulator in maintaining intracellular energy balance. Our study first demonstrated the existence of an AMPK-oxidized form (inactive form) in mammalian cells, which cannot be activated by AMPK upstream kinase (AMPKK). Both Cys130 and Cys174 are responsible for mediating disulfide bond formation within the AMPK subunit. Endogenous Trx1 is an essential cofactor that mediates AMPK activation during energy stress by maintaining Cys130 and Cys174 structural integrity and preventing AMPK oxidation. We further discovered that energy starvation, associated with AMPK activation, induced AMPK oxidation mediated by reactive oxygen species (ROS), which represents a novel negative regulatory feedback mechanism during AMPK activation. Co-existence of the active and inactive form of AMPK brings a forth between energy stress and oxidative stress. Furthermore, Trx1 is also upregulated by energy starvation both in vitro and in vivo through an AMPK dependent mechanism. We conclude that AMPK and Trx1 make a complex and stimulate the function of one another during energy starvation. This positive feed back loop acts against both energy and oxidative stress under ischemia. High fat diet (HFD) induced AMPK inactivation associated with increased AMPK oxidation, suggesting that disruption of this feed back loop exacerbates myocardial injury induced by FHD. Cardiac overexpression of Trx1 significantly reduced myocardial infarction in obese mice, indicating that restoration the activity of the AMPK-Trx1 loop maybe considered to treat myocardial ischemia in obese patients. The AMPK-Trx1 complex will be a new therapeutic target for energy and oxidative stress-related cardiovascular diseases.


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