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.
|Maejima, Yasuhiro; Chen, Yun; Isobe, Mitsuaki et al. (2015) Recent progress in research on molecular mechanisms of autophagy in the heart. Am J Physiol Heart Circ Physiol 308:H259-68|
|Yu, Qiujun; Lee, Chi Fung; Wang, Wang et al. (2014) Elimination of NADPH oxidase activity promotes reductive stress and sensitizes the heart to ischemic injury. J Am Heart Assoc 3:e000555|
|Hsu, Chiao-Po; Yamamoto, Takanobu; Oka, Shinichi et al. (2014) The function of nicotinamide phosphoribosyltransferase in the heart. DNA Repair (Amst) 23:64-8|
|Lee, Ahyoung; Jeong, Dongtak; Mitsuyama, Shinichi et al. (2014) The role of SUMO-1 in cardiac oxidative stress and hypertrophy. Antioxid Redox Signal 21:1986-2001|
|Sciarretta, Sebastiano; Volpe, Massimo; Sadoshima, Junichi (2014) NOX4 regulates autophagy during energy deprivation. Autophagy 10:699-701|
|Del Re, Dominic P; Sadoshima, Junichi (2014) Elucidating ERK2 function in the heart. J Mol Cell Cardiol 72:336-8|
|Shao, Dan; Zhai, Peiyong; Del Re, Dominic P et al. (2014) A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response. Nat Commun 5:3315|
|Wu, Changgong; Jain, Mohit Raja; Li, Qing et al. (2014) Identification of novel nuclear targets of human thioredoxin 1. Mol Cell Proteomics 13:3507-18|
|Ikeda, Yoshiyuki; Sciarretta, Sebastiano; Nagarajan, Narayani et al. (2014) New insights into the role of mitochondrial dynamics and autophagy during oxidative stress and aging in the heart. Oxid Med Cell Longev 2014:210934|
|Matsushima, Shouji; Tsutsui, Hiroyuki; Sadoshima, Junichi (2014) Physiological and pathological functions of NADPH oxidases during myocardial ischemia-reperfusion. Trends Cardiovasc Med 24:202-5|
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