Mechanisms of tumor-associated cardiac muscle damage under different variants of melanoma growth

Abstract

In case of the presence of a malignant process in an organism, the heart is subjected to an additional loading due to a unique combination of the external factors that is determined by the tumor biology and potentially cardiotoxic treatment actions and effects. It should be mentioned that cardiomyocytes have the same pathways of responding to stress and metabolic strategies as it is the case with the tumor cells, and this suggests that metabolic changes in the course of the tumor progression make their impact on the non-malignant tissue. Aim. The aim of our research work has been to study the level of the indices of the activity of free-radical processes and the hypoxia factor in cardiac mitochondria in mice under the different rates of the growth of B16 melanoma, growing either independently or against the background of chronic neurogenic pain. Materials and methods. In our experiment, we have used mice of both sexes of strain С57ВL/6 (n = 56) and strain C57BL/6-Plautm1.1Bug — ThisPlauGFDhu/GFDhu (with uPA gene-knockout) (n = 56). We have composed the following experimental groups: an intact animal group (♂ n = 7; ♀ n = 7); a reference group (♂ n = 7, ♀ n = 7) with reproduction of the model of chronic neurogenic pain (CNP); a comparison group (♂ n = 63, ♀ n = 63) with a standard subcutaneous inoculation of melanoma (В16/F10), upon 2 weeks of the tumor growth; the main test group (♂ n = 63, ♀ n = 63) (CNP+В16/F10) with melanoma transplanted 3weeks after reproduction of the CNP model, with a tumor growing time of 2 weeks. After decapitation of the animals, the heart was harvested and mitochondria were isolated using the differential centrifugation with a highspeed refrigerated centrifuge. In the prepared mitochondria specimens with the use of ELISA assays we have determined concentrations of SOD 2 (pg/mg protein), GPx-1 (ng/mg protein), MDA mcM/g protein); AOPP (mcM/g protein); 8-hydroxy 2’ deoxyguanosine (8-OHdG) (ng/mg protein); the amount of protein (mg/mL) has been determined with a biochemical assay method, namely with the Biuret assay (Olvex Diagnosticum, Russia). The obtained statistics data have been processed with software Statistica 10.0. Results. In the female mice of strain С57ВL/6, when comparing the studied data in cardiac mitochondria between the groups with the independent growth of melanoma and that in combination with CNP, we have revealed the higher levels of MDA increased by a factor of 1,8 (р < 0,05), АОРР increased by a factor of 1,7 (р < 0,05), 8-OHdG increased by a factor of 7,7, SOD 2 2,8 times higher and SOD 2/ GPx increased by a factor of 19,6 under the melanoma growth against the background of CNP. In this case, we have recorded lower values of GPx 1, namely, decreased by a factor of 6,9 and lower values of HIF, namely, reduced by a factor of 2,0 in cardiac mitochondria in female mice with combined pathology. In male mice we have recorded that the levels of SOD 2, MDA, 8-OHdG and SOD 2/GPx 1 are 1,5 times (р < 0,05), 1,3 times (р < 0,05), 5,5 times and 1,7 times (р < 0,05) higher than those found in cardiac mitochondria in the males under the independent melanoma growth. In this case, we should state that the HIF level is higher in cardiac mitochondria in the comparison group: it has been increased by a factor of 2,0. In the mutant mice of both sexes no differences in the studied data in cardiac mitochondria between the main test group and the comparison group have been revealed. Conclusion. The revealed imbalance between the reactive oxygen species (MDA, AOPP) and the hypoxia factor (HIF) leading to damage of mtDNA (increased 8-OHdG) in cardiac mitochondria determines the degree of damage of the cardiac muscle in the normal genotype mice, namely, in mice of strain C57BL/6 of both sexes in case of melanoma B16 growing against the background of chronic neurogenic pain. In the uPA gene-knockout mice of both sexes, CNP stimulates the growth of melanoma, but in this case no infarctions appear and the processes of free-radical oxidation are inhibited, which are stimulators of heart damages in the normal genotype mice.

Imprint

Oleg I. Kit, Alla I. Shikhlyarova, Elena M. Frantsiyants, Irina V. Neskubina, Irina V. Kaplieva, Valeria A. Bandovkina, Galina V. Zhukova, Lidia K. Trepitaki, Yulia A. Pogorelova, Natalia D. Cheryarina, Inga M. Kotieva, Sergey V. Shlyk, Alexandra A. Vereskunova, Marina A. Gusareva, Viktoria V. Pozdnyakova, Natalia A. Zakharova, Ekaterina S. Bosenko, Ekaterina I. Surikova. Mechanisms of tumor-associated cardiac muscle damage under different variants of melanoma growth. Cardiometry; Issue 24; November 2022; p.121-133; DOI: 10.18137/cardiometry.2022.24.121133; Available from: https://www.cardiometry.net/issues/no24-november-2022/mechanisms-tumor-associated-cardiac