Map of protein signaling pathways that went off course in DCM hearts. Credit: Uros Kuzmanov
An enlarged heart is a hallmark of dilated cardiomyopathy (DCM) and, despite being the most common inherited disease of the heart muscle, doctors don’t really know why it occurs. But that could now change as a new University of Toronto study begins to shine light on the molecular causes behind DCM. The study reveals widespread differences in protein biochemistry between healthy and diseased hearts. This expands our understanding of heart physiology and opens the door for future research that could improve detection and treatment of DCM.
Affecting all ages, the disease begins usually in adolescence and strikes 1 in 5 Canadians, with huge healthcare, economic and social costs. It occurs when a normal-looking heart begins to dilate, or stretch, for no apparent reason. This enlarged heart can no longer maintain the normal rhythm and pump the blood around the body, which leads to heart failure.
Professors Andrew Emili and Anthony Gramolinl mapped changes in protein signalling pathways in heart cells that lead to DCM. Proteins are the end products of genes, and they do most of the work in cells – Eg heart growth during development is controlled by complex signalling networks between thousands of different proteins. Their activity is often regulated by phosphorylation – a biochemical reaction where a phosphate group is added onto a protein to make it more, or less, active, or to change its position in the cell, or to mark it for destruction. By scanning the patterns of protein phosphorylation, they were able to study how sick hearts ramp up, or dampen, entire protein signalling pathways – thus becoming vulnerable to heart failure.
Kuzmanov used mice that carry a mutation, akin to one found in human patients, that makes them develop DCM. The teams collected heart samples from young adult healthy and mutant mice, at a time when their heart muscles just began to stretch. The researchers then ground the heart tissue to remove the proteins, which were fed into a mass spectrometer to be counted.
Based on the changes in the levels of thousands of phosphorylated proteins, they uncovered hundreds of signalling pathways that went off course in DCM hearts. This is the first comprehensive map of molecular signaling events that go awry in heart failure. Next, the teams will carry out similar analysis in human tissue. If, as expected, they can detect similarly robust changes in the same signalling pathways in patients’ hearts, then the human map could help scientists nail down promising new drug targets or biomarkers for early detection. “We expect to be able to detect specific changes in signalling pathways in different cardiac patients,” said Kuzmanov. “And our approach is not limited to the DCM—it could be applied to all heart disease.” http://scienmag.com/heart-signaling-map-sheds-light-on-the-molecular-culprits-behind-cardiovascular-disease/
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