ATP13A3 – a new critical gene for cardiac integrity and interventricular communication – implications for heart diseases with pressure overload.

• Applicant: Ekaterina Legchenko, Ph.D.
• Subject Area: Cardiology, Angiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 550401014

Changes in cellular metabolism are increasingly viewed to play an important role in the pathogenesis of multiple cardiovascular diseases. Recently, we have identified patients with mutations in the ATP13A3 gene that suffered from cardiovascular disease. ATP13A3 is a P5-type ATPase suggested to serve as polyamine transporter, predominantly bringing the precursor polyamine putrescine, but also spermine and spermidine into cells. Polyamines play a vital role in critical cell functions including cell differentiation and growth. Interestingly, a large increase in myocardial levels of putrescine and spermidine has recently been detected in myocardial infarction and pressure overload mouse models of human disease. The cellular origin of the polyamines and functional consequence of increased myocardial levels, however, remain unclear. In this project we aim to analyze whether ATP13A3 serves as a polyamine transporter in the cardiomyocytes and whether its dysfunction alters polyamine content, function, and metabolism of these cells. We are also aiming to analyze Atp13a3 mutant mice and examine the development of right and left ventricular hypertrophy/dysfunction by comprehensive cardiac phenotyping. We will identify transcriptional, metabolic and proteomic abnormalities caused by Atp13a3 depletion in the hypertrophied/failing hearts from mutant and control animals. Together with the results from cellular work, this will give mechanistic clues how ATP13A3 affects ventricular hypertrophy and whether it could serve as therapeutic target in the future. In addition, we will explore how the crosstalk between right and left ventricle is altered under pressure load and if ATP13A3 is a key mediator in this process. The project is likely to open new insights into the pathobiology of heart failure. It is designed to lay the groundwork for new precision medicine treatment approaches to tackle right and left ventricular failure in the future, especially, but not exclusively, for patients with a malfunctioning ATP13A3 gene.

• DFG Programme: Research Grants