Two commonly used FDA-approved antibiotics have been shown to induce mammalian cardiomyocyte proliferation and heart regeneration. Through a mixture of biochemical and computational screening, researchers from the lab of Hesham Sadek, MD, PhD, at the University of Texas Southwestern Medical Center identified paromomycin and neomycin as candidates to induce the proliferation of cardiomyocytes. Administering a combination of paromomycin and neomycin in adult mice and in pigs after cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved left ventricular systolic function and decreased scar formation.
The research article, “Identification of FDA-approved drugs that induce heart regeneration in mammals,” was published in Nature Cardiovascular Research.
The mechanics of postnatal heart development
Heart failure, a highly impactful disease affecting approximately 30 million individuals worldwide, occurs in adults due to the myocardium’s inability to self-repair following damage. Although cardiomyocyte turnover is normal in adult hearts, the current rate is insufficient to restore cardiac function after significant loss of cardiomyocytes, making this model unsuitable for therapeutic purposes.
However, newborn mammals and certain lower vertebrates possess a robust capacity to regenerate their hearts. Cardiomyocytes undergo proliferation to facilitate the restoration of normal heart function following damage. Unfortunately, mammals lose the ability to regenerate by postnatal day 7 (P7), which marks the end of cardiomyocyte proliferation.
After birth, the closure of fetal shunts leads to significant alterations in blood flow and oxygen levels. This triggers multiple pathways that facilitate a transition in the growth pattern of cardiomyocytes from hyperplasia to hypertrophy, leading to a permanent cessation of the cell cycle.
Eliminating the transcription factors Meis1 and Hoxb13 reverses adult cardiomyocyte cell cycle arrest and significantly enhances left ventricular function following myocardial infarction in mice. These findings indicate that stimulating the growth of heart muscle cells through inhibiting Meis1 and Hoxb13 transcriptional activity could be a promising approach for regenerating the heart.
Paromomycin and neomycin stimulate cardiomyocyte proliferation
In this study, Mahmoud Salama Ahmed, PhD, and Ngoc Uyen Nhi Nguyen, PhD, used screening tools spanning several disciplines, from X-ray crystallography to small and large animal studies, to find FDA-approved drugs that can block the activity of Meis1 and Hoxb13 genes and stimulate heart muscle cell growth and heart regeneration in living organisms.
Neomycin and paromomycin were identified as the top two candidates based on their ability to induce mitosis in neonatal rat ventricular myocytes (NRVMs) in a laboratory setting and their ability to inhibit the transcriptional activity of Meis1 and Hoxb13. The electrophoretic mobility shift assay (EMSA) revealed that the combination of two drugs can interfere with the DNA binding of both transcription factors. The binding of both drugs to Meis1 at the Hoxb13 interaction domain was confirmed by X-ray crystallography.
The authors provide multiple lines of evidence to support the claim that combining paromomycin and neomycin stimulates the growth of cardiomyocytes and facilitates heart regeneration. These assays encompassed quantification of the overall cell count and specific measurements of cell proliferation and lineage tracing. Paromomycin induced cardiomyocyte mitosis when used alone or in combination with neomycin. However, the combination of both drugs yielded the most significant enhancement in left ventricular ejection fraction in two mouse models of myocardial infarction.
Ultimately, the researchers investigated the capacity of these drugs, which have received approval from the FDA for human use, to assist in heart tissue regeneration in large mammals. A group of studies on pigs showed that giving them a mix of paromomycin and neomycin intravenously once a day, starting one week after an ischemia-reperfusion injury, made their left ventricular fractional shortening much better than it was one week after the injury and better than pigs that were given a vehicle. Adding paromomycin and neomycin together also increased markers of cardiomyocyte mitosis and decreased the size of scars after injury.
These findings bring the researchers closer to using paromomycin and neomycin in clinical trials for heart failure.
