If everything is not in its proper place in a heart cell, heart attack risk increases. This is the finding of a recent article published in Circulation by a team from the University of Iowa and collaborators at external institutions including Baylor College of Medicine in Houston, Texas. The team was interested in a previously suggested link between microtubule density and heart failure in human patients and experimental models of heart failure. “While it was known that changes in microtubules are linked to the progression of heart failure, no one understood how this was happening,” said Dr. Long-Sheng Song, lead researcher from the University of Iowa Carver College of Medicine.
Microtubules, which are proteins that allow trafficking inside cells, can be affected by drugs such as colchicine and taxol. Cholchicine, used to treat gout, lowers the risk of heart attack for patients; taxol, used to treat cancer, raises the risk of heart attack. The study found that taxol increases microtubule density, causing a specialized protein called junctophilin-2 (JP2) to be sent to the wrong place in the cell. “Changes in microtubule density directly affect where junctophilin-2 is located within the cell,” Song explained. “If junctophilin-2 is not in its proper destination, then the cell cannot function properly, which leads to the development and progression of heart failure.” Conversely, colchicine decreases microtubule density, keeps JP2 in its proper location, and protects normal heart muscle function.
JP2 is essential for transmitting electrical and chemical signals through cells to cause coordinated contraction of heart muscle. It contributes to normal organization of Transverse-tubules, which are mainly central to heart cells. Increased microtubule density causes JP2 to end up at the periphery of heart cells.
The team used a pressure overload-induced cardiomyopathy by transaortic banding mouse model of heart failure for the study, but the mis-distribution of JP2 has been found in failing human heart muscle, as well. Results from this study can therefore be translated into therapeutic benefits for humans. “The findings suggest that colchicine could be considered as a treatment for patients with heart failure,” says Song. “The study also suggests that future approaches targeting junctophilin-2 directly might be a potential strategy for treating heart failure.”
The research was supported by grants from the National Institutes of Health (HL090905, HL092235, HL079031, HL622494, HL70250, HL113001, HL085686), and the American Heart Association.