3.1.1 Research progress of O-Glycomics and heart disease
O-GlcNAcylation is a special sugar modification after protein transcription and translation, which is related to a variety of pathophysiological processes in cells[32]. The total level of O-GlcNAcylation is determined by the regulation of mitochondrial energy metabolism. The two key enzymes involved in this regulation process are O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA)[33].
Some researchers have found that in infarcted heart failure, the specific loss of OGT in cardiomyocytes will lead to a decrease in O-GlcNAc glycosylation, increase apoptosis and fibrosis, thereby aggravating cardiac remodeling and ultimately aggravating cardiac dysfunction and mortality, which indicates that elevated O-GlcNAc glycosylation may improve heart failure[34]. In addition, in patients with diabetes or hyperglycemia and myocardial dysfunction, studies have also found that the level of O-GlcNAc glycosylation is increased, and OGT inhibitors can improve pathological myocardial hypertrophy[35].
However, some studies have found that intracellular O-GlcNAcylation is significantly increased in heart failure. This seems to mean that O-GlcNAc glycosylation is harmful. Although increased O-GlcNAcylation is currently one of the hallmarks of heart failure, it is not clear whether excessive O-GlcNAcylation causes or promotes heart failure and cardiomyopathy[36]. Excessive O-GlcNAcylation can lead to cardiomyopathy, which may be due to the blockage of mitochondrial energy metabolism, while increasing OGA activity and reducing O-GlcNAcylation levels may alleviate heart failure and cardiomyopathy[37].
Increased O-GlcNAcylation in myocardium is associated with a variety of cardiovascular and metabolic diseases, such as aortic stenosis, hypertension, ischemia and diabetes[33, 34]. The research team led by Mark Anderson and Priya Umapathi of Johns Hopkins University in the United States published important research results in the top journal Circulation in the cardiovascular field, providing a transgenic mouse model that can independently control the level of O-GlcNAcylation in the myocardium to clarify that O-GlcNAcylation in the myocardium may not depend on pathological stress response. Elevated levels of O-GlcNAcylation in the myocardium can cause dilated cardiomyopathy and premature death, while overexpression of OGA in the myocardium can reduce the level of O-GlcNAcylation and specifically protect pathological cardiac hypertrophy[38].
This suggests that reducing excessive O-GlcNAcylation in myocardium may contribute to the treatment of heart failure, and O-GlcNAcylation is expected to become a new target for the treatment of cardiomyopathy, which is of great significance for clinical application. Related fields have been further explored with the efforts of Chinese scientists. Professor Zhang Zhenlu’s team found that glycosylation is an inevitable influencing factor for all NT-proBNP tests. The glycosylation ratio of proBNP is as high as 70% in chronic heart failure, which makes the detection value of NT-proBNP abnormally low, resulting in false negatives[39]. In addition, more than 30% of patients with chronic heart failure are clinically complicated with renal insufficiency. It should be noted that renal insufficiency can lead to abnormal elevation of NT-proBNP, causing false positives and interfering with clinical judgment[33]. For these patients, BNP detection should be preferred to obtain accurate and reliable test results (Figure 1).