Autophagy is a major mechanism of degradation for long-lived proteins and intracellular organelles. Autophagy plays an adaptive role under energy starvation, such as myocardial ischemia, thereby mediating cell survival, whereas autophagy associates with programmed cell death under some pathological conditions, such as reperfusion injury. Thus, it is essential to elucidate the function of autophagy in various pathophysiological conditions and to determine how autophagy is regulated in the heart. In a mouse model of myocardial infarction (MI), induced by permanent coronary ligation (PCL), although excessive activation of autophagy increases the mortality at an acute phase, downregulation of autophagy leads to cardiac dysfunction at a chronic phase. Mammalian sterile 20 like kinase 1 (Mst1), a potent stimulator of apoptosis and heart failure, strongly inhibits autophagy whereas FoxO1, which is activated by nutrient starvation and cardiac unloading, stimulates autophagy. The overall goal of this project is to elucidate both physiological and pathological functions of autophagy in the heart under stress and how autophagy is regulated by stress responsive signaling mechanisms in the heart. We hypothesize that: A) Strong induction of autophagy by Beclin 1 at an acute phase of MI is detrimental, whereas autophagy induced by FoxO1 at a chronic phase of MI is adaptive. B) Mst1 acts as an endogenous inhibitor of autophagy through direct protein-protein interaction with Beclin1, thereby causing an accumulation of protein aggregates through p62, an ubiquitin interacting protein. C) FoxOs are either deacetylated or upregulated by starvation and cardiac unloading and plays an essential role in mediating adaptive autophagy. These hypotheses will be tested, using (1) established experimental methods to evaluate autophagosome formation and autophagic flux in vitro and in vivo, (2) unique genetically altered mouse models, including cardiac specific and inducible Beclin1 knock down, atg7 KO, and FoxO1 KO mice and systemic p62 KO mice, (3) the mouse models of PCL and aortic debanding, (4) shRNA-mediated knock- down and proteomics. Our study will elucidate the role of autophagy in mediating both physiological and pathological functions under stresses and underlying signaling mechanisms regulating autophagy in the heart.
Autophagy, an important mechanism of protein degradation through lysosomes, plays an adaptive role in various pathophysiological conditions. Our study will elucidate the role of autophagy in mediating both physiological and pathological functions under stresses and underlying signaling mechanisms regulating autophagy in the heart. The knowledge obtained from this study may lead to better understanding of the mechanism of myocardial injury and heart failure and the development of novel strategies to treat patients with myocardial infarction and cardiomyopathy.
|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 :|
|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|
|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|
|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|
|Nah, Jihoon; Fernández, Álvaro F; Kitsis, Richard N et al. (2016) Does Autophagy Mediate Cardiac Myocyte Death During Stress? Circ Res 119:893-5|
Showing the most recent 10 out of 105 publications