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Researchers at the University of Toronto have found that a receptor expression-enhancing protein contributes to normal heart development and function by regulating the sarcoplasmic reticulum, a network of tubules found in cardiac muscle cells.

The sarcoplasmic reticulum is key in the development and progression of heart disease, governing biochemical changes, structural remodeling and deterioration. But how this membrane-bound system organizes itself is still mostly unknown – especially in cells with a highly differentiated or diverse network such as heart muscle cells, or cardiomyocytes.

“Our findings show that a protein called REEP5 plays a critical role in regulating cellular stress responses in heart muscle cells,” says Frank Shin-Haw Lee, a PhD student in the lab of Anthony Gramolini, an associate professor of physiology in U of T’s Faculty of Medicine who is based at the Ted Rogers Centre for Heart Research.

“When REEP5 is depleted, it destabilizes the heart and reduces the amount of blood the heart can pump on each contraction,” says Lee. “When we removed this protein in both mice and zebrafish, it distorted the structure and shape of cardiomyocytes and led to cardiac dysfunction.”

The journal Nature Communications .

When cardiomyocytes are under sustained stress from general dysfunction or disease, cellular pathways through the sarcoplasmic reticulum can lead to cell death and heart failure. Lee says that REEP5 is vital to the formation of the sarcoplasmic reticulum and to how it responds to stress and regulates calcium, which is essential for heart health.

A better understanding of how REEP5 functions in the heart may elucidate how heart failure develops amidst a sarcoplasmic reticulum in stress, Lee says.

The Gramolini lab worked with several other Toronto researchers on the study, including Ian Scott, a professor of molecular genetics at U of T and a senior scientist at the Hospital for Sick Children. The work builds on previous collaborative research from the labs of Gramolini, Scott and medical biophysics professor Thomas Kislinger in 2015, which created a blueprint of critical cell-surface and membrane-associated proteins in the heart.

Medical student Sina Hadipour-Lakmehsari was a co-first author on the current paper with Lee, and he says the findings may provide insight into heart disease in patients.

“It is clearly an important protein for cardiac development and function and, combined with future human studies, it may help us unearth new potential therapies,” Hadipour-Lakmehsari says, adding that the lab can continue to look at REEP5 in genetic studies to help shed light on diseases whose causes remain unknown.

“This study is among the first in the world to show that the REEP5 protein plays an essential role in the stress responses that often lead to heart failure,” adds Gramolini, who is also a scientist at Toronto General Hospital Research Institute, University Health Network. “Deciphering the complex layers of heart function on a cellular level will help us generate new therapeutic and preventative strategies for heart failure.”

The study received support from the Ted Rogers Centre Innovation Fund, the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research, among others.