心律失常性心肌病,SB21 z-bo 2020-09-19 340

　　Arrhythmic cardiomyopathy (ACM) (arrhythmic right ventricular myopathy/arrhythmic right ventricular dysplasia, also known as ARVC/ARVD) is a kind of myocardial tissue that is dominated by the right ventricle covered by adipose tissue. The onset of fibrous tissue replacement is relatively insidious, and is often accompanied by malignant arrhythmias. At present, eight gene mutations related to the disease have been identified, five of which encode desmosomal protein, the main pathogenic gene of ARVC. It encodes three independent desmosomal protein families, which play an important role in the connection between cells. , DSG and DSC of Cadoherin family members, PKP and PG of armadillo protein value members, and DSP of hemolysin protein member. However, the mechanism that causes the disease, especially the mechanism of arrhythmia, remains on the surface. In an article published on AnnTranslMed, the author studied the disease characteristics of different patients through innovative experimental models and successfully mastered the basic mechanism.

　　In the field of experimental myocardial research, due to the various advantages of the zebrafish model, more and more people choose zebrafish for experiments. The hearts of mammals and zebrafish have a lot in common. For example, very conservative heart structures include atria, ventricles, valves, and even similar cardiac conduction systems. The zebrafish's heart is small, but its electrocardiogram can be recorded 5 days after fertilization, just like the human electrocardiogram. In addition, the heart rate of zebrafish is closer to that of humans than that of mice, making it a suitable animal model for studying heart diseases such as QT syndrome and arrhythmia. In addition, the various potential activity parameters between humans and zebrafish are very similar. In the process of depolarization, which controls the sodium current of stroke, the buffer formed by the L-type calcium channel and the repolarized potassium current are very similar. The latter plays an important role in drug-induced arrhythmia, which does not exist in mice. After studying the disease using a zebrafish model, it was found that the overexpression of PKG2057del2 in zebrafish (which can lead to Naxos disease) indicates cardiac hypertrophy, peripheral edema and decreased heart rate output. it is. The most notable thing in this experiment is that after screening 4,200 small molecules with recombinant zebrafish, a drug that can prevent or even reverse all the above symptoms was successfully discovered. The drug SB216763 (SB21) is an inhibitor of glycogen synthesis kinase (GSK-3β) and an activator of the Wnt pathway. The Wnt pathway plays a very important role in various cellular processes, such as axon proliferation, cell transformation, heart growth and differentiation, and cell adhesion. From these data, it can be seen that the dislocation of GSK-3β downstream proteins and the changes in the triggering molecular signals of cardiomyocytes and myocardium were observed. Therefore, if the translocation of the protein can be suppressed and the changes in the expansion and contraction of the protein can be restored, an excellent antiarrhythmic effect can be obtained.

　　SB21 is expected to be a powerful drug for the treatment of ACM, but it contains the Wnt pathway, and the Wnt pathway plays a very important role in growth and development, so how to master this level is very important. Zebrafish cannot completely replace the mouse, but it does show some obvious benefits.