Reduction and oxidation (Redox) are defined by the gain and loss of electrons, respectively, both of which affect the structure and function of proteins. Cardiac stress increases reactive oxygen species (ROS), which oxidize proteins, thereby affecting a wide variety of cellular functions, including hypertrophy and cell death. Thioredoxin1 (Trx1) is a 12 kD protein that protects the heart from pathological hypertrophy and ischemia/reperfusion. Trx1 interacts with intracellular signaling molecules, and reduces oxidized cysteine residues, thereby modulating their function. Our long-term goal is to identify important substrates of Trx1 in the heart and elucidate the functional significance of the regulatory effect of Trx1 in response to clinically relevant stress. In order to identify novel targets of Trx1 durin myocardial ischemia, we generated transgenic mice with cardiac specific expression of a Trx1 trap mutant. One of the proteins we identified using this system was AMP-activated protein kinase (AMPK), a serine threonine kinase. AMPK is an important sensor of energy stress and positively regulates the catabolic process to maintain the energy level. We hypothesize that AMPK is subjected to cysteine oxidation during myocardial ischemia, which negatively regulates AMPK. Trx1 is an essential co-factor of AMPK, allowing AMPK to be activated during myocardial ischemia to promote cell survival by reducing the oxidized cysteines in AMPK. AMPK and Trx1 form a positive feedback loop to stimulate one another's functions during stress. We will: 1) elucidate the molecular mechanism by which cysteine oxidation during ischemia inactivates AMPK, 2) demonstrate the role of Trx1 as an essential co-factor of AMPK during myocardial ischemia, and 3) demonstrate that AMPK and Trx1 form a positive feedback mechanism to protect the heart against ischemia, but that their function is impaired in response to consumption of a high fat diet. We will use proteomic analyses of posttranslational modifications and unique genetically altered mouse models. Our study will elucidate how posttranslational oxidative modification of cysteine residues regulates the activity of AMPK during metabolic stress and show that Trx1 is a critical co-factor of AMPK in the protection of the heart against prolonged ischemia.
We will elucidate the molecular mechanisms by which oxidative stress modulates the functions of intracellular signaling molecules during myocardial ischemia and their functional significance. In particular, AMP-dependent protein kinase (AMPK), a molecule that acts as a fuel gauge in the heart, and thioredoxin 1 (Trx1), an anti- oxidant, stimulate one another's actions to protect the heart during myocardial ischemia. The cooperative function of the two molecules is attenuated by oxidative stress. We will investigate how the synergistic action of the two molecules can be restored during ischemia. Our study may provide an important clue as to how to develop a novel strategy to treat ischemic heart disease.
|Ikeda, Shohei; Mizushima, Wataru; Sciarretta, Sebastiano et al. (2018) Hippo Deficiency Leads to Cardiac Dysfunction Accompanied by Cardiomyocyte De-Differentiation During Pressure Overload. Circ Res :|
|Saito, Toshiro; Sadoshima, Junichi (2017) Unexpected Functional Consequences of the Loss of the Autophagy-Related Conjugation System. Circ Res 120:610-612|
|Mizushima, Wataru; Sadoshima, Junichi (2017) BAG3 plays a central role in proteostasis in the heart. J Clin Invest 127:2900-2903|
|Sciarretta, Sebastiano; De Falco, Elena; Frati, Giacomo et al. (2017) How to be young at heart? miR-22 as a potential therapeutic target to boost autophagy and protect the old myocardium. Ann Transl Med 5:52|
|Nagarajan, Narayani; Oka, Shinichi; Sadoshima, Junichi (2017) Modulation of signaling mechanisms in the heart by thioredoxin 1. Free Radic Biol Med 109:125-131|
|Sadoshima, Junichi (2017) Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School. Circ Res 121:1127-1129|
|Sadoshima, Junichi; Tomoike, Hitonobu (2017) What Should We Learn From the Recent Decline of Basic Cardiovascular Science in Japan? Circ Res 121:314-316|
|Oka, Shin-Ichi; Hirata, Tsuyoshi; Suzuki, Wataru et al. (2017) Thioredoxin-1 maintains mechanistic target of rapamycin (mTOR) function during oxidative stress in cardiomyocytes. J Biol Chem 292:18988-19000|
|Matsuda, Takahisa; Zhai, Peiyong; Sciarretta, Sebastiano et al. (2016) NF2 Activates Hippo Signaling and Promotes Ischemia/Reperfusion Injury in the Heart. Circ Res 119:596-606|
|Matsushima, Shouji; Zablocki, Daniela; Tsutsui, Hiroyuki et al. (2016) Poldip2 negatively regulates matrix synthesis at focal adhesions. J Mol Cell Cardiol 94:10-12|
Showing the most recent 10 out of 116 publications