A Molecular Switch Governing Pathological Changes
in Heart Muscle Cell Shape

By Adrienne Mueller, PhD

Too Much Pressure or Too Much Volume

Because heart muscle cells are responsible for the contractions that pump our blood, their shape is very important. Having the right shape allows them to move blood effectively. Stressing heart muscle cells causes them to change their shape in a way that impairs heart function. One common source of stress is an obstruction to the outflow of the heart, which exposes heart muscle cells to excessive pressure. When heart muscle cells experience pressure overload, they respond by growing wider. Another source of stress is caused by heart chamber enlargement, which often occurs as a result of a heart attack. An enlarged heart attempting to pump abnormally high volumes of blood causes heart muscle cells to be exposed to a different type stress, to which they respond by growing longer. Both of these changes in heart muscle cell shape—growing wider in response to pressure overload and growing longer in response to volume overload—spell trouble for heart function and increase your risk of heart failure.

In order to develop therapies to prevent changes in heart muscle cell shape, we need to understand the mechanisms that govern cell growth. A group of investigators from several institutions led by Stanford Cardiovascular Institute-affiliated co-first author Jinliang Li, PhD and co-senior author Michael Kapiloff, MD, PhD, decided to investigate the role of a protein called serum response factor (SRF) in this process.

In response to pressure or volume overload, SRF regulators change the balance of modified and unmodified SRF. Imbalances in SRF then lead to heart muscle cells growing either too wide or too long.

A Surprising Switch

In their study, recently published in Circulation, the investigators discovered not only that SRF is involved in heart muscle cell remodeling in response to stress, but that SRF acts as a switch that determines whether heart muscle cells grow predominantly in width or in length. Two different proteins modify SRF by either adding or removing a tiny phosphate group. When the phosphate group is present, SRF promotes heart cells growth in width, and when the phosphate group is absent, SRF promotes heart cell growth in length. As Dr. Kapiloff describes, “Stress often causes heart muscle cells to grow, but what is especially exciting about this result is that we have identified a molecular switch that specifically directs growth in one direction versus another.”

Another surprising finding of this study is the magnitude of SRF’s involvement. SRF is primarily known for its critical role in determining heart cell identity during development. As Dr. Kapiloff puts it, “It’s a molecule that makes heart cells heart cells.” What these investigators discovered therefore is that modification of a protein that determines cell fate is responsible for stress-induced changes in cell shape.

Therapies for Heart Failure

“By flipping the SRF switch, we witnessed a 10% change in cell size in just 24 hours. That translates to a 20% change in heart weight, which unchecked over time could have serious, potentially fatal, consequences,” noted Dr. Kapiloff. Identifying ways to prevent SRF from being switched too far in either direction, therefore, has significant therapeutic potential. As part of their study, the authors developed molecular interventions targeting the proteins that modify SRF. Their interventions were able to prevent pathological heart cell remodeling in response to pressure or volume overload and, by doing so, improve heart function. Translating these interventions into therapies for heart failure that can be deployed in the clinic is work that is currently being pursued by the new start-up company Cardiac RSK3 Inhibitors, LLC founded by Dr Kapiloff.

Other Stanford Cardiovascular Institute-affiliated authors who contributed to this study include Xueyi Li, Yang Li, Qian Yu, Hrishikesh Thakur, John W. MacArthur Jr, and Y. Joseph Woo.

Dr. Jinliang Li

Dr. Michael Kapiloff