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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102738-03
Application #
8242792
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Adhikari, Bishow B
Project Start
2010-04-15
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$498,255
Indirect Cost
$178,861
Name
University of Medicine & Dentistry of NJ
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
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Tong, Mingming; Sadoshima, Junichi (2016) Mitochondrial autophagy in cardiomyopathy. Curr Opin Genet Dev 38:8-15
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Nagarajan, Narayani; Oka, Shinichi; Sadoshima, Junichi (2016) Modulation of signaling mechanisms in the heart by thioredoxin 1. Free Radic Biol Med :
Shirakabe, Akihiro; Zhai, Peiyong; Ikeda, Yoshiyuki et al. (2016) Response by Shirakabe et al to Letter Regarding Article, ""Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload-Induced Mitochondrial Dysfunction and Heart Failure"". Circulation 134:e75-6
Shirakabe, Akihiro; Fritzky, Luke; Saito, Toshiro et al. (2016) Evaluating mitochondrial autophagy in the mouse heart. J Mol Cell Cardiol 92:134-9

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