Unlocking another piece of the puzzle: novel approach maps signaling pathways underlying heart failure

Researchers at the Ted Rogers Centre for Heart Research have developed an innovative approach to better understanding the complex signaling mechanisms underlying heart failure. A recent publication in the Proceedings of the National Academy of Sciences (PNAS) offers valuable insights into the phosphorylation-driven regulation of protein networks in heart failure patients. While heart failure affects millions worldwide, the underlying signaling pathways have remained largely unexplored – until now.

Proteins are regulated by phosphorylation – a biochemical reaction where a phosphate group is added to a protein to make it more, or less, active, to change its position in the cell, or to mark it for destruction. Phosphorylation plays a pivotal role in regulating protein function and activity, yet few studies have investigated the cardiac phosphoproteome in the context of human heart failure. The research team led by Drs. Cristine Reitz, Uros Kuzmanov, and Anthony Gramolini, scientists at the Ted Rogers Centre for Heart Research, set out to bridge this knowledge gap by profiling the phosphoproteome from different types of heart failure: dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM).

Building on work previously published by the Gramolini Lab, the researchers used a comprehensive proteomic and phosphoproteomic approach, to analyze over 5,000 total proteins and more than 13,000 corresponding phosphorylation sites in tissue samples from healthy and cardiomyopathic hearts.

The results revealed unique proteomic and phosphoproteomic profiles for the cardiomyopathic tissue samples, suggesting phosphorylation-driven regulation plays a role in the development and prognosis of heart disease. This mapping not only exposed shared disruptions but also highlighted unique alterations specific to different types of heart failure. Notably, the study identified a hyperphosphorylation cluster associated with DCM in a protein called αT-catenin. The researchers further validated this finding in other experimental models, demonstrating the significance of αT-catenin phosphorylation in maintaining cardiac structure, function, and the organization of cardiomyocytes in the heart.

Dr. Cristine Reitz, a researcher at the Centre and the lead author of the study, highlighted the importance of their findings. “This work underscores the value of our novel approach in understanding the complex signaling pathways related to heart failure,” she explains.

Armed with this knowledge, researchers and clinicians can tailor treatments to the individual, based on the specific molecular irregularities triggering the heart failure. This approach has the potential to revolutionize heart failure treatment, leading to more effective interventions and improved patient outcomes.

“This study delivers new insights into the field, demonstrating the power of a combined proteomic and phosphoproteomic technique to further elucidate how protein signaling pathways change in complex diseases,” notes Dr. Anthony Gramolini, a principal investigator at the Centre driving this research. “We’re unlocking another piece of the puzzle.”

This study was led by investigators at the Ted Rogers Centre (Dr. Anthony Gramolini, Dr. Uros Kuzmanov, and Dr. Cristine Reitz) in collaboration with researchers from the University of Alberta (Dr. Gavin Oudit) to access actual human heart tissues through the Human Explanted Heart Program (HELP) and Human Organ Procurement and Exchange (HOPE) biobank programs, as well as researchers and their teams from York University (Dr. Peter Backx) and The Centre for Network Systems Biology at Boston University (Dr. Andrew Emili).

This project was funded by the Ted Rogers Centre Translational Biology and Engineering Program, the Canadian Institutes of Health Research, and University of Toronto’s Medicine by Design initiative, as well as Ted Rogers Centre and CIHR fellowships to researchers in the Gramolini lab.