Study: slow release drug tt-10 can improve recovery after heart attack

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a2b0732152928e1 - Study: slow release drug tt-10 can improve recovery after heart attack

a heart attack kills cardiomyocytes, resulting in scars that weaken the heart, often leading to eventual heart failure. The lack of muscle repair is due to the very limited proliferative capacity of mammalian cardiomyocytes, except for the short period before and after birth

therefore, a drug product named tt-10 plays a role through the components of Hippo Yap signaling pathway to stimulate the proliferation of cardiomyocytes, which is considered to be promising for the treatment of heart attack. A few years ago, researchers injected tt-10 intraperitoneally into a mouse heart attack model, initially promoted the proliferation of cardiomyocytes, and showed a decrease in the size of cardiomyocyte death areas (called infarcts) one week after administration. However, these early improvements resulted in deterioration of cardiac function at a later time point

therefore, Dr. jiananyi “Jay” Zhang and his colleagues in the Department of Biomedical Engineering at the University of Alabama Birmingham raised a simple question. What happens if tt-10 is loaded into nanoparticles made of polylactic acid co glycolic acid (or PLGA) to slowly release tt-10

as reported by UAB researchers in JCI insight, sustained release is indeed beneficial. Nanoparticle mediated sustained-release delivery of tt-10 enhances the efficacy and persistence of tt-10 therapy in repairing myocardium in mouse heart attack model

Study: slow release drug tt-10 can improve recovery after heart attack

compared with the mice treated with normal saline, empty nanoparticles or directly with tt-10 solution, the injection of tt-10 nanoparticles into the infarcted myocardium can improve cardiac function — through the significant improvement of ejection fraction and functional shortening, And the significant decrease of end systolic diameter and end diastolic diameter. In addition, similar to the measurements of the other three groups, the infarct size and heart weight / body weight ratio of the heart treated with tt-10 nanoparticles were significantly reduced. All these measures showed that the cardiac function of tt-10 nanoparticle group was improved

the researchers also measured the effects of tt-10 on cardiomyocyte biology and several markers of cell reproduction, including in culture and mouse heart disease model

human induced pluripotent stem cell cardiomyocytes grown in different concentrations of tt-10 showed increased molecular markers of proliferation, S phase of cell cycle (when cells replicate their genomic content), M phase of cell cycle (when cells divide replicated DNA) and cell division (when the cytoplasm of two daughter cells is divided into two). The activity peak appeared when the concentration of tt-10 was 10 to 20 μ mol

cultured cardiomyocytes also showed a significant decrease in programmed cell death or apoptosis, and the proportion of cardiomyocytes with Yap in the nucleus increased significantly. The researchers said that the presence of Yap in the nucleus, that is, it actively helps gene expression, is consistent with the role of Hippo Yap signal in cardiac regeneration

compared with the other three treatment groups, the hearts treated with tt-10 nanoparticles in the mouse heart attack model had significantly more marginal cardiomyocytes one week after infarction, which showed cell proliferation, M-phase growth and markers of Yap nuclear location. The border area refers to the area next to the infarction. In addition, tt-10 nanoparticle therapy seems to promote the growth of blood vessels, called angiogenesis

Study: slow release drug tt-10 can improve recovery after heart attack(1)

UAB said that this shows that the improvement of myocardial recovery observed in mice treated with tt-10 nanoparticles seems to be due at least in part to the activation of Hippo Yap signal and the proliferation of cardiomyocytes

the researchers said: “Therefore, our results show that PLGA nanoparticles can be used to improve the treatment and management efficiency of many cardiovascular drugs. In addition, although the animals in our current investigation treat tt-10 nanoparticles by direct intramyocardial injection during thoracotomy, PLGA nanoparticles can be fully compatible with less traumatic clinical delivery methods, such as catheter-based or echo guidance Transthoracic myocardial injection. “