Dangerous losses
The loss of the Y chromosome led to heart disease in male mice
Slava Gomenyuk, N+1
Male mice whose hematopoietic cells had their Y chromosome removed developed fibrotic changes in the muscle tissue of the heart with a further decrease in organ function. According to scientists in an article published in the journal Science (Sano et al., Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality), Y-chromosome-deprived cardiac macrophages more actively triggered and supported the process of myocardial fibrosis. In addition, scientists have found a link between the loss of the Y chromosome in blood cells and death from heart disease in humans.
The Y chromosome in humans is responsible for the development of the male-type organism in the prenatal period and for spermatogenesis in adulthood. Its other effects on the body are poorly understood due to difficulties in understanding its genetic variability. However, there are a number of studies that have studied the mosaic loss of the Y chromosome in blood cells - a condition in which there is no Y chromosome in part of the hematopoietic cells (most often such a mutation occurs in leukocyte cells). The frequency of such loss increases with age and smoking experience. It was recently reported that mosaic Y-chromosome loss is found in 40 percent of 70-year-old men and 57 percent of 93-year-old men. Some scientists even suggest considering the loss of this chromosome as a marker of biological aging.
Epidemiological studies have shown that the loss of the Y chromosome in blood cells is associated with a decrease in life expectancy and an increase in the frequency of various age-related diseases, including solid tumors and Alzheimer's disease. In addition, it has been associated with diseases of the cardiovascular system, including myocardial infarction and stroke of the brain. However, due to the descriptive nature of these studies, it is difficult to say whether the loss of the Y chromosome in blood cells can be considered the cause of the development of these conditions.
Scientists from the USA, Japan and Sweden, led by Soichi Sano from the University of Virginia, using CRISPR-Cas9 technology, modeled the loss of the Y chromosome in hematopoietic blood stem cells, which were then transplanted into male mice. In the study group of mice, the proportion of leukocytes without a Y chromosome ranged from 49 to 81 percent (on average, 64.9± 4.0 percent), which corresponds to the levels of such cells in men with fibrotic changes in the heart. This condition persisted for 12 months and affected myeloid cells to a greater extent (which also corresponds to observations in older men).
No obvious deviations in blood parameters were observed either in mice from the control group or in mice without a Y chromosome in blood cells. However, the latter lived significantly less than healthy mice (p=0.0124). Successive echocardiographic studies revealed accelerated development of age-related cardiomyopathy with greater cardiac dysfunction in mice without a Y chromosome. The loss of the Y chromosome led to an increase in the area of myocardial fibrosis and the number of fibroblasts.
The development of fibrosis led to an increase in the filling pressure of the left ventricle, which indicates diastolic myocardial dysfunction. These changes in the heart were observed with constantly low blood pressure in mice without a Y chromosome. Also, the concentrations of renin and angiotensin II in such mice did not significantly differ from the concentrations in healthy mice.
15 months after bone marrow transplantation in mice without a Y chromosome, scientists observed a more intensive development of fibrosis in the interstitial lung (p<0.05). Histological examination of renal tissue also showed a greater degree of fibrosis in 15-month-old mice without a Y chromosome compared to their healthy peers (p< ,005). Finally, the assessment of cognitive functions revealed violations of short-term working memory in Y-maze tests and recognition of new objects in aging (15 months) mice without a Y chromosome. Such disorders did not occur in young (two months old) mice without a Y chromosome.
After that, male mice aged 12 to 16 weeks (four weeks after bone marrow transplantation) had their aortic diameter narrowed in order to reproduce the condition of non-ischemic heart failure. In mice without a Y chromosome, according to echocardiography, scientists found a greater progressive decrease in cardiac function compared to healthy mice after narrowing of the aorta. Biochemical blood analysis revealed a significantly greater increase in markers of heart failure in mice without a Y chromosome (p<0.05).
Histological examination showed greater interstitial and perivascular fibrosis in the left parts of the heart in such mice (p<0.001). In addition, the number of fibroblasts in them was also higher (p<0.0001). At the same time, scientists found no differences in the number of endothelial cells of the heart or the average cross-sectional area of myocytes between the groups. These facts indicate the predominant cellular effect of Y-chromosome loss, aimed at controlling the number of fibroblasts in the heart.
Also, in the hearts of mice without a Y chromosome after narrowing the diameter of the aorta, scientists found a greater number of cardiac macrophages CCR2+ compared to healthy mice (p<0.05). Assuming that functional properties were changed in cardiac macrophages derived from hematopoietic stem cells without a Y chromosome, mice were injected with an antibody to the granulocyte-1 receptor, which blocks the migration of neutrophils and monocytes into damaged tissue. In mice without a Y chromosome with a narrowed aorta, the administration of antibodies slowed the development of cardiac dysfunction (p<0.05) and reduced heart mass. Also, an antibody to the granulocyte-1 receptor reduced the number of fibroblasts in the heart.
In addition, additional analyses showed that the loss of the Y chromosome contributed to the expression of the transcript encoding transforming growth factor-b1 in fibrous macrophages. Its blockade with monoclonal antibodies slowed down the development of cardiac dysfunction, reduced the manifestations of congestion in the lungs and restored normal heart mass. In addition, the number of fibroblasts and deposition of extracellular matrix decreased.
Among other things, scientists analyzed data from the British Biobank to find a link between the loss of the Y chromosome in leukocytes and the risk of death from cardiovascular diseases. It turned out that the loss of the Y chromosome in leukocytes increases the risk of death from all cardiovascular diseases in men by 0.54 percent with an increase in the proportion of leukocytes without a Y chromosome by one percent (p=0.0010). With additional consideration of several variables, the analysis showed that in men whose proportion of leukocytes without a Y chromosome exceeded 40 percent, the risk of death from any disease of the cardiovascular system during follow-up (on average 11.5 years) increased by 31 percent (p=0.0382).
The most common diseases that led to death were hypertension, heart failure, congestive heart failure, aneurysm and aortic dissection. In the extended analyses, the scientists did not find a link between the loss of the Y chromosome and polyethological heart diseases leading to heart failure. However, the loss of the Y chromosome was associated with death caused by diseases of the aorta and peripheral arteries (p=0.0082).
Thus, scientists believe that there is a causal relationship between the mosaic loss of the Y chromosome in blood cells and age-related cardiac dysfunction in men. It manifests itself in an increase in the fibrotic activity of cardiac macrophages without a Y chromosome, which leads to proliferation and activation of cardiac fibroblasts and excessive production of connective tissue. According to scientists, further research should focus on proving such links directly on humans in order to develop new methods for the diagnosis and treatment of heart diseases in the elderly in the future.
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