Previous research at UT Southwestern Medical Center had found that the newborn mammalian heart can heal itself, while the adult heart doesn’t possess the same capabilities. Recent research by the same group of scientists has revealed why the heart loses this capability in adulthood.
It is well understood that the main function of the heart is to pump oxygen-rich blood to the body. Unfortunately, oxygen is a highly-reactive oxidizing compound that forms toxic substances with many other compounds. This oxidizing property has now been discovered to be the culprit for the loss of the heart’s ability to heal itself in adults. Simply put, the oxygen-rich postnatal environment creates cell cycle arrest of cardiomyocytes.
Dr. Hesham Sadek, Assistant Professor of Internal Medicine at UT Southwestern and senior author of the study notes, “Knowing the key mechanism that turns the heart’s regenerative capacity off in newborns tells us how we might discover methods to reawaken that capacity in the adult mammalian heart.”
The oxygen-rich environment presented to the neonate causes a build up of mitochondria. Mitochondria are the site of oxygen and glucose utilization that generates ATP, which in turn creates production of massive amounts of free radicals, thus leading to DNA damage and ultimately causing cell cycle arrest.
Sadek and colleagues have revealed a previously unrecognized protective mechanism that mediates cardiomyocyte cell cycle arrest, which occurs as a consequence of aerobic respiration. Sadek notes, physiologically speaking, mammals had to make a decision as to whether to be energy efficient or retain the ability to regenerate the heart: “The choice was clear. More than any organ in the body, the heart needs to be energy efficient in order to pump blood throughout life.”
Cardiac muscle contains more mitochondria than any other cells in the body, and as such uses 30 percent of the body’s total oxygen in the resting state alone. The energy produced from massive amounts of oxygen utilization comes with a great price, in the form of DNA oxidation that causes cardiac muscle cells to be unable to divide and regenerate.
Sadek, along with co-first authors Dr. Bao “Robyn” Puente, postdoctoral trainee in Pediatrics, and Dr. Wataru Kimura, visiting senior researcher in Internal Medicine, subjected mice to a low-oxygen environment and found that cardiomyocytes divided longer than usual. The researchers found that the opposite was true when mice were born into a higher-oxygenated environment. The cardiomyocytes stopped dividing earlier than unusual.
Earlier, Sadek found that if he removed a portion of the mouse heart during the first week after birth, the removed portion grew back wholly and correctly. On the other hand, an adult heart was irreversibly damaged by removal of even a small amount of tissue. As the mammalian heart is post-mitotic (can’t create daughter cells) shortly after birth, this creates a huge barrier in cardiovascular medicine. Having some understanding of what arrests the cardiomyocyte cell cycle may lead to understanding of how to proliferate heart muscle cells in the adult.