WELCOME TO THE SADOSHIMA LAB
Cardiovascular disease is the number one cause of death in developed countries. We are interested in the molecular mechanisms of heart failure and, in particular, have been focusing on the cellular mechanisms that control its progression. We have made significant contributions to a better understanding of the molecular mechanisms of heart failure through discovery of key signaling mechanisms, including the Hippo signaling pathway, autophagy/mitophagy, and the thiol signaling pathway.
VISION
The PI became interested in heart failure during his cardiology training. Having witnessed the deaths of many patients suffering from heart failure, he feels strongly that it is important to more deeply understand the underlying molecular mechanisms that promote weakening of cardiac muscles. Understanding precisely how the structure and function of molecules are affected during cardiac stress should allow for the development of safe and effective interventions to treat heart failure patients. Basic science studies based upon clinically relevant and important questions, together with multidisciplinary and collaborative approaches, should lead to game changing discoveries that would allow patients to achieve healthier lives.
MISSION
We will make significant contributions to the progress of cardiovascular medicine. One of our most important goals is to discover novel and specific signaling mechanisms involved in the progression of heart failure that can be directly translated into better treatment of heart failure patients. We publish our results in journals of the highest quality and present our results at international conferences. We are committed to training next generation scientists so that they efficiently acquire strong expertise and contribute to the field in a continuous fashion.
APPROACH
We use cutting edge molecular biological and cell biological methods both in vitro and in vivo. Our studies using genetically altered mouse models combined with microsurgical interventions are state-of-the-art. We routinely use multiple-omics approaches combined with bioinformatic approaches.
We are currently investigating 1) cellular and organelle quality control mechanisms, including autophagy and mitophagy, 2) regulation of growth and death of cardiomyocytes by the Hippo signaling pathway, 3) the molecular mechanisms of diabetic cardiomyopathy, 4) regulation of cellular signaling mechanisms through thiol-disulfide exchange reactions, and 5) the regulation of mitochondrial function through Sirt1.
IMPACT
The PI has contributed several game changing concepts to the field of basic heart failure research.
During his early career, the PI made significant contributions to a better understanding of the signaling mechanisms of cardiac hypertrophy and heart failure in response to mechanical stress. He discovered that mechanical forces activate signaling mechanisms similar to those activated by GPCRs and that autocrine production of angiotensin II mediates stretch-induced cardiac hypertrophy (Cell 1993). What is currently known regarding the molecular mechanism of cardiac hypertrophy was summarized recently (Nat Rev Cardiol 2018)
The PI subsequently discovered that mammalian sterile 20-like kinase 1 (Mst1) plays a critical role in mediating apoptosis of cardiomyocytes in the heart (JCI 2003). Mst1 is a key molecule in the Hippo pathway, an evolutionarily conserved signaling pathway that controls organ size and tissue regeneration. This was the first report to show the involvement of the Hippo pathway in the regulation of growth and death in the heart. Subsequent studies in his laboratory and others have solidified the importance of the Hippo pathway in the pathogenesis of heart failure and myocardial injury (Circ Res 2008; JCI 2010; Nat Ned 2013; Nat Commun 2014; Mol Cell 2014; Cell Report 2015; Circ Res 2015; JCI Insight 2016; Circ Res 2019).
The PI also discovered that thioredoxin 1 reduces disulfide bonds at key cysteine residues in HDAC4 (Cell 2008) and AMPK (Cell Metabolism 2014), thereby inducing nuclear localization and activation, respectively. He developed mice with cardiac-specific expression of a thioredoxin 1 trapping mutant to identify targets of thioredoxin during stress and determined that AMPK and mTOR oxidized during cardiac stress are relevant targets of thioredoxin in the heart. These studies were the first to show that oxidative stress directly modulates the function of signaling molecules, thereby affecting growth and death of cardiomyocytes. He also investigated the molecular mechanisms of aging and discovered several key mechanisms that co-regulate cardiac aging and stress resistance (Circ Res 2007). His laboratory was the first to investigate the function of Sirt1 in the heart (Circ Res 2004; Circ Res 2009; Circ Res 2010; Circ 2010; Cell Metabolism 2011; Circ Heart Failure 2015). He recently discovered that high fat diet consumption induces Ser280 phosphorylation of PPARa through activation of GSK-3b, which in turn induces selective upregulation of genes involved in fatty acid uptake but not fatty acid oxidation (Cell Metabolism 2019). The study describes novel mechanisms of lipotoxicity.
His laboratory is also one of the first groups to show the functional significance of autophagy in the heart (PNAS 2006; Circ Res 2007). He discovered that autophagy in the heart is negatively regulated by mTOR and Mst1 and that suppression of autophagy by these mechanisms is detrimental during metabolic stress and heart failure (Circulation 2012; Nature Medicine 2013; JACC 2018). He has been leading the field of autophagy in the heart through publications (69 papers) and meeting presentations, including at NIH organized conferences for autophagy in 2018 and mitophagy in 2019. He is an Associate Editor of Autophagy, an organizer of a Keystone Symposium on mitochondria, metabolism and the heart (2017), and the North American coordinator of a Fondation Leducq Transatlantic Network of Excellence focusing on autophagy (2016-2020). He has shown that removal of damaged mitochondria by autophagy is suppressed during pressure overload and that this contributes to the development of heart failure (Circ Res 2015; Circ 2016; Nat Med 2017). He recently reported novel molecular mechanisms of mitophagy in the heart in response to myocardial ischemia (JCI 2019) and high fat diet consumption (Circ Res 2019). The role of mitophagy and autophagy in the heart was summarized recently (Compr Physiol 2017; Annu Rev Physiol 2018).
SELECTED PUBLICATIONS
1. Nakamura M, Liu T, Husain S, Zhai P, Warren JS, Hsu CP, Matsuda T, Phiel CJ, Cox JE, Tian B, Li H and Sadoshima J. Glycogen Synthase Kinase-3alpha Promotes Fatty Acid Uptake and Lipotoxic Cardiomyopathy. Cell Metab. 2019;29:1119-1134.
2. Tong M, Saito T, Zhai P, Oka SI, Mizushima W, Nakamura M, Ikeda S, Shirakabe A and Sadoshima J. Mitophagy Is Essential for Maintaining Cardiac Function During High Fat Diet-Induced Diabetic Cardiomyopathy. Circ Res. 2019;124:1360-1371.
3. Saito T, Nah J, Oka SI, Mukai R, Monden Y, Maejima Y, Ikeda Y, Sciarretta S, Liu T, Li H, Baljinnyam E, Fraidenraich D, Fritzky L, Zhai P, Ichinose S, Isobe M, Hsu CP, Kundu M and Sadoshima J. An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia. J Clin Invest. 2019;129:802-819.
4. Ikeda S, Mizushima W, Sciarretta S, Abdellatif M, Zhai P, Mukai R, Fefelova N, Oka SI, Nakamura M, Del Re DP, Farrance I, Park JY, Tian B, Xie LH, Kumar M, Hsu CP, Sadayappan S, Shimokawa H, Lim DS and Sadoshima J. Hippo Deficiency Leads to Cardiac Dysfunction Accompanied by Cardiomyocyte Dedifferentiation During Pressure Overload. Circ Res. 2019;124:292-305.
5. Sciarretta S, Yee D, Nagarajan N, Bianchi F, Saito T, Alenti V, Tong M, Del Re DP, Vecchione C, Schirone L, Forte M, Rubattu S, Shirakabe A, Boppana VS, Volpe M, Frati G, Zhai P, Sadoshima J. Trehalose-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction. J Am Coll Cardiol. 2018;71:1999-2010.
6. Shirakabe A, Zhai P, Ikeda Y, Saito T, Maejima Y, Hsu CP, Nomura M, Egashira K, Levine B and Sadoshima J. Drp1-dependent mitochondrial autophagy plays a protective role against pressure-overload-induced mitochondrial dysfunction ad heart failure. Circulation. 2016;133:1249-63.
7. Sciarretta S, Zhai P, Maejima Y, Del Re DP, Nagarajan N, Yee D, Liu T, Magnuson MA, Volpe M, Frati G, Li H and Sadoshima J. mTORC2 regulates cardiac response to stress by inhibiting MST1. Cell Rep. 2015;11:125-36.
8. Del Re DP, Matsuda T, Zhai P, Maejima Y, Jain MR, Liu T, Li H, Hsu CP and Sadoshima J. Mst1 Promotes Cardiac Myocyte Apoptosis through Phosphorylation and Inhibition of Bcl-xL. Mol Cell. 2014;54:639-50.
9. Shao D, Oka S, Liu T, Zhai P, Ago T, Sciarretta S, Li H and Sadoshima J. A Redox-Dependent Mechanism for Regulation of AMPK Activation by Thioredoxin1 during Energy Starvation. Cell Metab. 2014;19:232-45.
10. Maejima Y, Kyoi S, Zhai P, Liu T, Li H, Ivessa A, Sciarretta S, Del Re DP, Zablocki DK, Hsu CP, Lim DS, Isobe M and Sadoshima J. Mst1 inhibits autophagy by promoting Beclin1-Bcl-2 interaction Nature Med. 2013;19:1478-88.
11. Oka S, Alcendor R, Zhai P, Park JY, Shao D, Cho J, Yamamoto T, Tian B and Sadoshima J. PPARalpha-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway. Cell Metab. 2011;14:598-611.
12. Del Re DP, Matsuda T, Zhai P, Gao S, Clark GJ, Van Der Weyden L and Sadoshima J. Proapoptotic Rassf1A/Mst1 signaling in cardiac fibroblasts is protective against pressure overload in mice. J Clin Invest. 2010;120:3555-67.
13. Ago T, Liu T, Zhai P, Chen W, Li H, Molkentin JD, Vatner SF and Sadoshima J. A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy. Cell. 2008;133:978-93.
14. Yan L, Vatner DE, O'Connor JP, Ivessa A, Ge H, Chen W, Hirotani S, Ishikawa Y, Sadoshima J* and Vatner SF*. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell. 2007;130:247-58. (* Co-corresponding authors)
15. Sadoshima J, Xu Y, Slayter HS and Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993;75:977-84.
FUNDING
NIH, American Heart Association, Fondation of Leducq
Dr. Jihoon Nah is a finalist for the Melvin L. Marcus Early Career Investigator Award competition at the AHA Scientific Sessions in November 2020. He will present “Inhibition of Autosis Attenuates Ischemia/Reperfusion Injury in the Heart.”
Dr. Jun Sadoshima received the AHA’s 2020 Merit Award.
Check out our Department's recent feature in Circulation Research: http://circres.ahajournals.org/content/121/10/1127.long
Please visit the Leducq Autophagy website: http://www.leducq-autophagy.org/
Please Join us at BCVS Scientific Sessions 2020 in Chicago. July 27, 2020 - July 30, 2020. A pre-symposium for young investigators will be held on July 26, 2020.