Researchers in the Michael E. DeBakey Department of Surgery at Baylor College of Medicine, the QIMR Berghofer Medical Research Institute in Brisbane, Australia, and collaborating institutions report a groundbreaking discovery in cardiac regeneration that offers new hope for the treatment of ischemic heart failure. Published in npj Regenerative Medicine, the study reveals a novel approach to promoting cardiomyocyte proliferation. Previous studies showed that calcium plays an important role in cardiomyocyte proliferation. In the current study, scientists explored how modulating calcium influx in cardiomyocytes would affect their proliferation. Scientists found that preventing calcium influx in cardiomyocytes enhances the expression of genes involved in cell proliferation.
They prevented calcium influx by inhibiting L-Type Calcium Channel (LTCC), a protein that regulates calcium in these cells. The LTCC contains five subunits: the pore-forming subunit, α1, and different auxiliary subunits, α2, β, γ, and δ. The α1 subunit allows the passage of Ca2+ ions through LTCC into CMs, while the auxiliary subunits modify the function of the channel. RRAD is a member of the Ras-related small G proteins and an endogenous regulator of LTCC activity that binds directly to the β subunit of the LTCC, thereby controlling its current. Recent studies have provided insights into the downstream impact of Ca2+ signaling, highlighting the role of the calcium-dependent serine/threonine phosphatase calcineurin in mediating cell-cycle arrest of postnatal cardiomyocytes.
Calcineurin directly links Ca2+ signaling to protein phosphorylation status upon increased intracellular Ca2+ and plays an essential role in numerous signaling processes. This includes proliferation, where forced expression of activated calcineurin (CnA) causes a premature switch from hyperplasic to hypertrophic growth. In contrast, genetic ablation of calcineurin B prolongs the window of heart cells proliferation and induces the cell cycle in mature cardiac cells partly through the induction of nuclear translocation of the transcription factor HoxB13. This transcription factor is an homeotic protein, regulating cellular embrionality and maturation. The study demonstrates that both pharmacological and genetic inhibition of LTCC can induce cardiomyocyte replication by modulating the activity of calcineurin.
Moreover, a small molecule inhibitor for calcineurin, FK506, promotes CM proliferation. Calcineurin acts by dephosphorylating Hoxb13 at serine-204 causing translocation to the nucleus and leads to cell cycle arrest. Expression of both calcineurin and Hoxb13 are significantly higher in p7 postnatal CMs, which coincides with cell cycle arrest during development. These reported data, in combination with our current study, further establish the role of the calcineurin/Hoxb13 axis in regulating CM cell cycle activity. One interesting point is that a well known LTCC inhibitor is nifedipine, currently used to treat high blood pressure. Scientists’ research highlights the importance of targeting calcium signaling pathways to unlock the regenerative potential of the heart and opens new avenues for developing cardiac regenerative therapies, potentially transforming the treatment landscape for patients suffering from heart failure.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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