While the many ways that heart disease develops and progresses is complex, research has shown that one particular area is key: the sarcoplasmic reticulum (SR). The SR governs many critical functions in every cell – but is also responsible for biochemical changes, structural remodeling, and deterioration when disease is present.

Yet, how the SR structures or organizes itself is still quite unknown – particularly in cells with a highly differentiated network: like hear, like cardiomyocytes in the heart.

A new study from the Gramolini lab at the Ted Rogers Centre for Heart Research – in collaboration with SickKids senior scientist Ian Scott – has shone a new light into this area. It describes how a particular protein contributes to normal heart development and heart function, and how it regulates formation, maintenance, and function of the SR there.

What we now know about REEP5

That protein is called REEP5, the subject of their paper newly published in Nature Communications, and it has for years been the focus of Frank Shin-Haw Lee, a University of Toronto research trainee who earned one of the first Ted Rogers Centre’s Education Fund awards.

Lee has been investigating the role of REEP5 in maintaining the integrity and function of highly differentiated SR in the heart, and how it may contribute to heart failure.

“Our findings show that REEP5 plays a critical role in regulating cellular stress responses in heart muscle cells,” says Lee, who is a member of the Ted Rogers Centre’s Translational Biology and Engineering Program. “When REEP5 is depleted, it destabilizes the heart and reduces the amount of blood it is able to pump on each contraction. When we removed this protein in both mice and zebrafish, it distorted the structure and shape of cardiomyocytes and lead to cardiac dysfunction.”

When cardiomyocytes are under sustained stress from disease or dysfunction, cellular pathways through the SR can ultimately lead to cell death and to heart failure. This research team believes that REEP5 is a vital part of how the SR forms, how it responds to stress, how it regulates calcium (essential for heart health) and, ultimately, how the heart itself functions and develops. The more we can understand how REEP5 functions in the heart, the more we can see how heart failure may develop amidst a SR in stress.

Possible new therapies on the horizon

Sina Hadipour-Lakmehsari, co-first author and U of T medical student, says these findings provide new insight into heart disease in patients. “It is clearly an important protein for cardiac development and function and, combined with future human studies, we may begin to unearth new potential therapies,” Hadipour-Lakmehsari says. “In the lab, we can continue studying 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,” says Anthony Gramolini, principal investigator and professor of physiology at U of T. “Deciphering the complex layers of heart function on a cellular level will help us generate new therapeutic and preventative strategies for heart failure.”

This research was funded by a Ted Rogers Centre Innovation Fund seed grant to Profs. Gramolini and Scott, a Natural Science and Engineering Research Council grant and a Canadian Institutes of Health Research grant to Prof. Gramolini.

Top photo: Harhsa Murthy, Frank Shin-Haw Lee, Sina Hadipour-Lakmehsari
Middle photo: Anthony Gramolini, Lee, Murthy, Hadipour-Lakmehsari, Ian Scott