TH1834, a TIP60 inhibitor, protected human stem cell-derived cardiomyocytes and cardiac organoids from reperfusion injury after simulated infarction, extending to human tissue an effect previously shown only in mice

TH1834, a TIP60 inhibitor, protected human stem cell-derived cardiomyocytes and cardiac organoids from reperfusion injury after simulated infarction, extending to human tissue an effect previously shown only in mice

Restoring blood flow after a heart attack needs to happen as quickly as possible, but the return of oxygen itself inflicts additional damage on the heart muscle. A team from SUNY Upstate Medical University and Syracuse University grew cardiac tissues from human stem cells, simulated this type of injury, and tested the compound TH1834 on them.

Cardiovascular disease kills more people than any other cause worldwide: in 2022, roughly 19.8 million people died from it, nearly a third of all deaths, with 85% caused by heart attack and stroke. A heart attack destroys heart muscle in two stages: first while the vessel is blocked, and then again at the moment blood flow is restored. The abrupt return of oxygen overloads cells with calcium, triggers a burst of reactive oxygen species, and temporarily shuts down mitochondria, the cell's energy-generating organelles. This second wave is called reperfusion injury, and it is exactly what a new study published on September 17 set out to suppress.

TIP60 is an enzyme that attaches chemical marks (acetyl groups) to histones, the proteins that package DNA. Through this modification, TIP60 activates the DNA damage response program, which halts cardiomyocyte division. The same laboratory demonstrated this mechanism in neonatal mice in 2021, and in the adult heart after myocardial infarction in 2022. In infarcted mice, the already-available compound TH1834 provided the same protective effect. TH1834 is a derivative of pentamidine, a drug used against sleeping sickness and leishmaniasis since the 1930s and 1940s, still prescribed today for Pneumocystis pneumonia in immunocompromised patients. In the early 1980s, the rising number of physician requests for pentamidine helped U.S. clinicians recognize the emerging HIV/AIDS epidemic.

All of this had been tested only in mice. Conventional human cardiomyocytes derived from stem cells are not suitable for this kind of experiment: they are too immature and too resistant to oxygen deprivation. The authors matured the cells over several days using a specialized culture medium, and only after that step could simulated ischemia actually damage them. Twenty-four hours of oxygen deprivation followed by reoxygenation caused cell death, a spike in reactive oxygen species, loss of functional mitochondria, and disrupted calcium signaling, the signal that drives each cycle of contraction and relaxation in a cardiomyocyte.

At a dose that did not disrupt the rhythm of contractions (a higher dose did disrupt it), TH1834 corrected nearly all of these effects: more cells survived, mitochondria were preserved, and calcium signaling and contractility recovered. TIP60 turned out to play a role beyond cell division as well. It is linked to the HIF1A-ARNT-PDK1 pathway, which holds the cell in an "oxygen is still absent" state even after oxygen has already returned. TH1834 suppresses this pathway. Once the pathway is blocked, the cell simultaneously ramps up mitochondrial respiration and its capacity to extract energy from glucose anaerobically, instead of remaining locked into one mode. The same result was reproduced in cardioids: three-dimensional miniature structures composed of multiple cardiac cell types and organized more closely to real tissue than a flat monolayer of identical cells.

Pentamidine, a close relative of TH1834, has been approved for use in humans for decades, for a different indication. The most immediate practical question is whether pentamidine or its derivatives can be administered in the first minutes after a heart attack, the window that determines how much heart muscle can be saved. The timing of intervention determines the outcome just as sharply for TIP60 itself: in its closest relative, a gene in the roundworm C. elegans, early suppression extended lifespan, while late suppression shortened it and worsened paralysis.