Modulating autophagy to treat CV disease

Brought to you by the Fondation Leducq Transatlantic Network of Excellence

Sadoshima Lab

Principal Investigator:

Junichi Sadoshima, MD, PhD

Leducq Lab Members: 

Toshiro Saito, MD, PhD (Leducq Fellow)
Gihoon Nah, PhD (Leducq Fellow)
Risa Mukai, PhD (Leducq Fellow)
Mingming Tong, MS
Narayani Nagarajan, MS

Contribution to the network:

The Sadoshima Lab has a long-standing expertise in the molecular/signaling mechanisms of heart failure with particular focuses on autophagy, the Hippo pathway, and oxidative stress. Our group contributes to this network’s expertise in autophagy and mitophagy in the heart and mouse models of heart disease.

The goal of our studies in the network is to understand the role of autophagy and mitophagy in the regulation of death and survival of cardiomyocytes in response to pathologically relevant stresses in the heart, such as high blood pressure and ischemia/reperfusion.

Our hypothesis is that autophagy plays both protective and detrimental roles in the heart in a stimulus-dependent manner. Mitophagy is downregulated in the failing heart, which in turn deteriorates mitochondrial functions. Excessive autophagy during ischemia/reperfusion induces autotic cell death in cardiomyocytes.

Significance: We will elucidate the molecular mechanisms and upstream signaling mechanisms by which mitophagy is regulated in cardiomyocytes during heart failure. This project should allow us to identify specific interventions to normalize mitophagy and attenuate mitochondrial dysfunction in the failing heart. Whether excessive activation of autophagy induces death of cardiomyocytes is controversial. Our study will clarify the contribution of autophagy to death of cardiomyocytes and how autotic death is induced in the heart in response to stress. This study should lead to the development of novel interventions to prevent death of cardiomyocytes during stress.