Researchers at Baylor College of Medicine and Australia’s QIMR Berghofer Medical Research Institute have discovered a novel approach to stimulating the regeneration of heart tissue, a breakthrough that could lead to better treatments for people with ischemic heart failure. The research, published in npj Regenerative Medicine, showed how manipulating calcium influx to cardiomyocytes could stimulate their proliferation, potentially helping the heart heal after injury.
“When the heart cannot replace injured cardiomyocytes with healthy ones, it becomes progressively weaker, a condition leading to heart failure. In this study, we investigated a new way to stimulate cardiomyocyte proliferation to help the heart heal,” said senior author Riham Abouleisa, PhD, an assistant professor in the division of cardiothoracic surgery at Baylor College of Medicine and co-corresponding author of the study.
The heart’s inability to regenerate damaged tissue has hampered efforts to develop treatments for heart failure. Under normal circumstances, cardiomyocytes are post-mitotic, exiting the cell cycle and ceasing to proliferate after reaching maturity. This makes it difficult for the heart to recover after damage caused by ischemia, a condition where the heart muscle is deprived of oxygen due to restricted blood flow. The discovery that calcium plays a pivotal role in controlling cell proliferation could offer a method to stimulate regeneration in heart cells.
For their research, the investigators focused on L-type calcium channels (LTCCs), proteins that regulate the entry of calcium ions into cardiomyocytes. They found that by inhibiting calcium influx through LTCC they could promote cardiomyocyte division by affecting calcineurin, a calcium-dependent enzyme known to regulate the cell cycle.
“We found that preventing calcium influx in cardiomyocytes enhances the expression of genes involved in cell proliferation,” Abouleisa said. “We prevented calcium influx by inhibiting LTCC, and our findings suggest that LTCC could be a target for developing new therapies to induce cardiomyocyte proliferation and regeneration.”
The study shows that pharmacologic blockers or genetic methods to inhibit LTCC enhance cardiomyocyte proliferation by interfering with calcineurin (a protein that helps regulate the immune system and cellular stress responses) activity, leading to an environment that promotes cell division.
There are some hurdles to overcome, however, to translating these findings to the clinic. Perhaps the most significant hurdle is ensuring that the manipulation of calcium channels can stimulate cell proliferation without adversely affecting heart function.
“One of the major limitations of altering intracellular Ca2+ levels is the clinical applicability of such an approach in treating ischemic heart failure in humans,” the researchers wrote in the discussion section of the study. The challenge is to find a delicate balance where calcium manipulation can regenerate heart tissue without disrupting the heart’s contractile function.
Another challenge is ensuring that any potential treatments can be safely delivered to the heart. The researchers noted that the direct genetic manipulation of LTCC is not feasible due to the lethal effects it can have on embryos.
The next steps in the team’s research will involve refining the methods to transiently inhibit LTCC activity in cardiomyocytes while avoiding long-term effects on heart performance which will be conducted in animal models to evaluate the long-term viability and safety of these therapies.
