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).

His group has shown recently that phosphorylation of Bcl-xL at Ser14 in response to acute pressure overload plays an essential role in mediating compensatory hypertrophy by inducing the release of Bcl-xL from IP3Rs, alleviating the negative constraint of Bcl-xL upon the IP3R-NFAT pathway (Nat Commun 2023).

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).

YAP promotes aerobic glycolysis (the Warburg effect) during the acute phase of pressure overload stress, thereby protecting the heart through production of macromolecules for compensatory hypertrophy and activation of cell survival mechanisms (JCI 2022). Although YAP plays a protectively role in the heart in many occasions, inadvertent activation of YAP induces de-differentiation of cardiomyocytes (Circ Res 2019) and dysregulation of autophagy (JCI 2021) and, thus, it becomes detrimental.

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 was invited to present the overview of autophagy in the heart at Oxoford Longevity Project (2022) and Journal of Cardiovascular Aging (2023).

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).

His laboratory is the first to report that Sirt1, a member of the sirtuin family, plays a protective role in the heart and the cardiomyocytes therein (Circ Res 2004). His laboratory is also investigating NAD+ metabolism, an essential co-factor activating Sirt1, and Nampt, a rate limiting enzyme producing NAD+ through the salvage pathway, which play an important role in protecting the heart during myocardial ischemia (Circ Res 2009). Exogenous application of NMN, a precursor of NAD+, or caloric restriction protects the heart by mimicking ischemic preconditioning and activating Sirt1 (PLoS One 2014).

His laboratory also investigates the role of autophagy in cardiac aging (Circ Res 2016). The laboratory is currently investigating the connection between autophagy and aging/senescence in the heart. In collaboration with the members of the Leducq autophagy network (http://www.leducq-autophagy.org), the laboratory is investigating the role of autophagy stimulators and caloric restriction mimetics upon healthy aging (JACC 2018; Nat Med 2016).