When a heart attack strikes, the body scrambles to repair the damage. A critical part of this process involves cardiac fibroblasts (CF), specialized cells that help maintain the heart’s structure. But when these cells become overactive, they can produce too much scar tissue. This excess production leads to cardiac fibrosis—a major contributor to heart failure.
A team led by Long-Sheng Song, MD, professor in the Division of Cardiovascular Medicine, and Jinxi Wang, PhD, research assistant professor in the same division, uncovered a surprising player in the repair process: a protein called junctophilin-2 (Jph2). Their findings, published in Circulation, reveal how Jph2 helps regulate CF activity and could open new doors for treating heart disease.
Why cardiac fibroblasts matter
After a heart attack, CFs migrate to the damaged area, producing extracellular matrix (ECM) proteins that form scar tissue. This initial repair is crucial—without it, the heart’s structure would weaken. However, if CFs overproduce, excessive scarring stiffens the heart, which impairs its function and increases the risk of heart failure and sudden cardiac death.
Scientists have long known CFs play a key role in heart disease progression, but their underlying mechanisms remain unclear. Song’s team set out to explore how calcium signaling, a process critical for cell function, affects CF behavior.
The unexpected role of Junctophilin-2
Jph2 was already known for its role in heart muscle cells through enabling proper contraction. But Wang discovered an unexpected finding: Jph2 is present in CFs and essential for their function.
Using genetically modified mice and cell studies, the researchers found that without Jph2, CFs could not properly activate or produce scar tissue. They also struggled to form new blood vessels after injury, a key part of the healing process.
“Jph2 acts like a molecular bridge between plasma membrane and intracellular organelle,” Wang explained. “It helps maintain calcium balance in fibroblasts, which is crucial for their repair functions.”
Implications for heart disease treatment
“The findings suggest that targeting Jph2 in CFs could help control fibrosis, potentially preventing excessive scarring while still allowing necessary repair,” said Wang.
Song’s team plans to investigate whether temporarily boosting or blocking Jph2 at specific times after injury could improve cardiac outcomes. “The big question now is how we can fine-tune Jph2 activity to optimize healing,” Song said.
Looking ahead
This study is the first to link Jph2 to cardiac fibroblast function, offering a new perspective on heart repair. Future research could explore drugs or gene therapies that modulate Jph2 to treat or even prevent heart failure.
“Understanding these cellular mechanisms brings us closer to better treatments for patients,” Song said. “The goal is to help the heart heal without letting scarring take over.”
Wang primarily conducted the research in Song’s group. Other contributors Song cited include Daniela Sarahi Yang Bennett, Emma J. Echard, Biyi Chen, Grace Ciampa, Weiyang Zhao, Qian Shi, Jin-Young Yoon, Robert M. Weiss, Chad E. Grueter, Duane D. Hall, and Barry London. The study was supported by funding from the American Heart Association, National Heart, Lung and Blood Institutes, and the US Department of Veterans Affairs.