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Background The strategy of adaptation of the human body in microgravity is largely associated with the plasticity of cardiovascular system regulatory mechanisms. During long-term space flights the changes in the stroke volume of the heart are observed, the heart rate decreases, the phase structure of cardiac cycle is readjusted The purpose of this work was to clarify urine proteome changes associated with the initial condition of the heart rate autonomic regulation mechanisms in cosmonauts who have participated in long space missions. Urine proteome of each cosmonaut was analyzed before and after space flight, depending on the initial parameters characterizing the regulatory mechanisms of the cardiovascular system. Results The proteins cadherin-13, mucin-1, alpha-1 of collagen subunit type VI (COL6A1), hemisentin-1, semenogelin-2, SH3 domain-binding protein, transthyretin and serine proteases inhibitors realize a homeostatic role in individuals with different initial type of the cardiovascular system regulation. The role of significantly changed urine proteins in the cardiovascular homeostasis maintenance is associated with complex processes of atherogenesis, neoangiogenesis, activation of calcium channels, changes in cell adhesion and transmembrane properties, changes in extracellular matrix, participation in protection from oxidative stress and leveling the effects of hypoxia. Therefore, the concentrations of these proteins significantly differ between groups with dominant parasympathetic and sympathetic influences. Conclusion The space flight induced urine proteome changes are significantly different in the groups identified by heart rate autonomic regulation peculiarities before space flight. All these proteins regulate the associated biological processes which affect the stiffness of the vascular wall, blood pressure level, the severity of atherosclerotic changes, the rate and degree of age-related involution of elastin and fibulin, age-related increase in collagen stiffness, genetically determined features of elastin fibers. The increased vascular rigidity (including the aorta) and of myocardium may be regarded as a universal response to various extreme factors. Significant differences in the semi-quantitative analysis of signal proteins between groups with different types of autonomic regulation are explained by a common goal: to ensure optimal adaptation regardless of age and of the genetically determined type of responses to the extreme environmental factors effects. Electronic supplementary material The online version of this article (10.1186/s12918-019-0688-9) contains supplementary material, which is available to authorized users.