MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Drug Discovery

Background:

• Heart disease remains a leading global cause of mortality and morbidity.
• Targeting intracellular pathways responsible for cardiomyocyte death is crucial but lacks clinical validation.
• Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is implicated in cardiac dysfunction.

Purpose of the Study:

• To investigate the role of MAP4K4 in cardiomyocyte death.
• To develop and validate a novel therapeutic strategy targeting MAP4K4 for heart protection.
• To assess the utility of human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) in preclinical drug discovery.

Main Methods:

• Utilized hiPSC-CMs to model human heart cell death.
• Employed MAP4K4 gene silencing to determine its necessity in oxidative stress-induced cell death.
• Developed and tested the small-molecule inhibitor DMX-5804 in hiPSC-CMs and a mouse model of ischemia-reperfusion injury.

Main Results:

• MAP4K4 is essential for oxidative stress-induced death in hiPSC-CMs.
• DMX-5804 treatment rescued hiPSC-CM survival, mitochondrial function, and calcium cycling.
• DMX-5804 significantly reduced ischemia-reperfusion injury in mice by over 50%.

Conclusions:

• MAP4K4 is a viable therapeutic target for preventing human cardiac cell death.
• hiPSC-CMs serve as a valuable platform for preclinical drug discovery in cardiovascular medicine.
• Targeting MAP4K4 offers a promising strategy to enhance cardiomyocyte survival and treat heart disease.