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. 2022 Aug 8;9(8):254.
doi: 10.3390/jcdd9080254.

Doxycycline Attenuates Doxorubicin-Induced Cardiotoxicity by Improving Myocardial Energy Metabolism in Rats

Danielle Dantas  1 , Amanda Gomes Pereira  1 , Anderson Seiji Soares Fujimori  1 , Ana Paula Dantas Ribeiro  1 , Carol Cristina Vágula de Almeida Silva  1 , Marina Gaiato Monte  1 , Camila Renata Corrêa  2 , Ana Angélica Fernandes  3 , Silmeia Garcia Zanati Bazan  1 , Paula Schmidt Azevedo  1 , Marcos Ferreira Minicucci  1 , Sergio Alberto Rupp de Paiva  1 , Leonardo Antônio Mamede Zornoff  1 , Bertha Furlan Polegato  1
Affiliations

Doxycycline Attenuates Doxorubicin-Induced Cardiotoxicity by Improving Myocardial Energy Metabolism in Rats

Danielle Dantas et al. J Cardiovasc Dev Dis. .

Abstract

Aim: Evaluate the influence of doxycycline, an anti-inflammatory and matrix metalloproteinase (MMP) inhibitor, on the attenuation of chronic doxorubicin-induced cardiotoxicity in rats.

Methods: We allocated male Wistar rats into four groups: control (C), doxorubicin (D), doxycycline (inhibitor of MMP, IM), and Dox + doxycycline (DIM). Groups IM and DIM received doxycycline (5 mg/kg, IP) once a week for 4 weeks. In addition, 48 h after every doxycycline injection, groups D and DIM received Dox (5 mg/kg, IP). We performed echocardiogram and evaluated TIMP-4 and collagen I protein expression, MMP-2 activity, and oxidative stress and myocardial metabolism.

Results: Doxorubicin promotes left atrium (LA) and left ventricle (LV) dilatation and decreases in LV fractional shortening, which was improved by doxycycline. Moreover, doxycycline attenuated the LV cardiomyocyte hypertrophy and collagen type I expression. Doxorubicin increased phosphofructokinase and decreased beta-hydroxyacyl Co-A dehydrogenase, pyruvate dehydrogenase, citrate synthase, and ATP synthase activity, which was partially attenuated by doxycycline. Lastly, doxycycline improved antioxidant enzyme activity in the DIM group.

Conclusion: Doxorubicin increases oxidative stress and promotes changes in myocardial energy metabolism, accompanied by structural and functional changes. Doxycycline attenuated the doxorubicin-induced cardiotoxicity, at least in part, through changes in myocardial energy metabolism.

Keywords: MMP-2; TIMP-4; collagen I; doxycycline; myocardial energy metabolism; oxidative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Body weight and chow intake. C, control group (n = 18); D, group treated with Dox (n = 20); IM, group treated with doxycycline (n = 19); DIM, group treated with Dox + doxycycline (n = 21). Initial, body weight immediately before the beginning of the experiment. We measured first food intake 1 week after drug administration. p-value, comparison between groups in week 4 by two-way ANOVA; pD, p-value for Dox effect; pIM, p-value for doxycycline effect; pi, p-value for the interaction between the factors Dox and doxycycline.
Figure 2
Figure 2
Collagen I and TIMP-4 protein expression. C, control group (n = 9); D, group treated with Dox (n = 8); IM, group treated with doxycycline (n = 9); DIM, group treated with Dox + doxycycline (n = 8); K, kaleidoscope molecular weight standard; UA, arbitrary units; p-value, two-way ANOVA; pD, p-value for Dox effect; pIM, p-value for doxycycline effect; pi, p-value for the interaction between the factors Dox and doxycycline.
Figure 3
Figure 3
MMP-2 activity. rMMP-2, MMP-2 recombinant used as a positive control; C, control group (n = 11); D, group treated with Dox (n = 8); IM, group treated with doxycycline (n = 8); DIM, group treated with Dox + doxycycline (n = 9); UA, arbitrary units; p-value, two-way ANOVA; pD, p-value for Dox effect; pIM, p-value for doxycycline effect; pi, p-value for the interaction between the factors Dox and doxycycline.
Figure 4
Figure 4
Histology and Cardiomyocyte Sectional Area. C, control group (n = 8); D, group treated with Dox (n = 8); IM, group treated with doxycycline (n = 8); DIM, group treated with Dox + doxycycline (n = 8); p-value, two-way ANOVA; pD, p-value for Dox effect; pIM, p-value for doxycycline effect; pi, p-value for the interaction between the factors Dox and doxycycline; #, different from C group; $, different from D group.
Figure 5
Figure 5
Energy myocardial metabolism. C, control group (n = 11); D, group treated with Dox (n = 9); IM, group treated with doxycycline (n = 9); DIM, group treated with Dox + doxycycline (n = 10). p-values are from a two-way analysis of variance; pD, p-value for Dox effect; pIM, p-value for doxycycline effect, pi, p-value for the interaction between the factors Dox and doxycycline; #, different from C group; $, different from D group; &, different from IM group.
Figure 6
Figure 6
Oxidative stress. C, control group (n = 11); D, group treated with Dox (n = 9); IM, group treated with doxycycline (n = 9); DIM, group treated with Dox + doxycycline (n = 10). p-value, two-way ANOVA; pD, p-value for Dox effect; pIM, p-value for doxycycline effect; pi, p-value for the interaction between the factor Dox and doxycycline; #, different from C group; $, different from D group; &, different from IM group.
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