Dilated cardiomyopathy (DCM), which is characterized by enlarged ventricles and decreased systolic function, is one of the important causes of heart failure. Most patients with dilated cardiomyopathy develop end-stage heart failure, and the survival rate within two years of diagnosis is less than 60% due to the lack of effective drugs. Recently, Xu Dachun/Xu Yawei, Department of Cardiology, Shanghai Tenth People’s Hospital, and Wei Ke, a professor at the School of Life Science and Technology of Tongji University, jointly published a paper in the journal “Circulation”, describing a protein molecule with special functions, Jmjd4, which can effectively empower cardiomyocytes and maintain the homeostasis of cellular energy metabolism, which is expected to become a new therapeutic target for dilated cardiomyopathy and other metabolic dysfunctional heart diseases.
It was found that the Jmjd4 protein exerts a “key assistant” in myocardial protection. Photo courtesy of the research team
In the face of difficult dilated cardiomyopathy, academic research in recent years has focused on the field of epigenetics, and a class of protein molecules called “domain proteins” Jmjd has entered the attention of researchers, and previous studies have confirmed that this type of protein plays an important role in the pathological process of cardiac hypertrophy and fibrosis. Jmjd protein is a large family, of which the “old four” Jmjd4 can make DNA “translate” into protein This process ends as soon as possible, so what role does it play in the energy metabolism of cardiomyocytes? To this end, the team focused on Jmjd4.
The researchers analyzed the expression of Jmjd4 in human dilated cardiomyopathy, mouse myocardial hypertrophy and myocardial infarction tissues, and found that its expression was significantly upregulated in heart disease, indicating that Jmjd4 is likely to be an important effector protein in the progression of heart failure. Through gene knockout, the researchers made the cardiomyocytes of experimental mice unable to synthesize Jmjd4 protein, and found that the mice had dilated cardiomyopathy, which was accompanied by severe pathological remodeling while ventricular dilation, which was consistent with the pathological manifestations of patients with clinical center failure. It can be seen that the Jmjd4 protein has a protective effect on heart failure, but the mechanism is not clear.
The research team also used whole transcriptome sequencing, co-immunoprecipitation and combined mass spectrometry to find that the pyruvate kinase 2 isotype (Pkm2), the “key assistant” of Jmjd4 protein to exert a protective role in myocardium, is highly correlated with the energy metabolism of cells. It is speculated that it acts on the cell’s energy supply station – mitochondria, injecting more energy into the damaged cardiomyocytes of the lesion, thereby greatly improving the repair efficiency and improving the prognosis.
In order to verify the above hypothesis, the researchers used a substance that can stimulate pyruvate kinase 2 to exert higher biological activity in mice, and found that the heart failure symptoms of mice were significantly improved, indicating that pyruvate kinase 2 is likely to be a universal target for metabolic intervention treatment of dilated cardiomyopathy.
The research results provide a new idea for the treatment of dilated cardiomyopathy – the use of special protein molecules to inject energy into the diseased cells can effectively maintain cardiomyocytes and cardiac functional homeostasis, thereby delaying or even reversing the course of the disease. (Source: China Science News, Zhang Shuanghu, Huang Xin)
Related paper information:https://doi.org/10.1161/CIRCULATIONAHA.123.064121
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