» Articles » PMID: 35096991

Trpc6 Promotes Doxorubicin-Induced Cardiomyopathy in Male Mice With Pleiotropic Differences Between Males and Females

Abstract

Doxorubicin is a widely used and effective chemotherapy, but the major limiting side effect is cardiomyopathy which in some patients leads to congestive heart failure. Genetic variants in have been associated with the development of doxorubicin-induced cardiotoxicity, suggesting that TRPC6 may be a therapeutic target for cardioprotection in cancer patients. Assessment of deficiency to prevent doxorubicin-induced cardiac damage and function was conducted in male and female B6.129 and Trpc6 knock-out mice. Mice were treated with doxorubicin intraperitoneally every other day for a total of 6 injections (4 mg/kg/dose, cumulative dose 24 mg/kg). Cardiac damage was measured in heart sections by quantification of vacuolation and fibrosis, and in heart tissue by gene expression of and . Cardiac function was determined by echocardiography. When treated with doxorubicin, male -deficient mice showed improvement in markers of cardiac damage with significantly reduced vacuolation, fibrosis and expression and increased expression in the heart compared to wild-type controls. Similarly, male -deficient mice treated with doxorubicin had improved LVEF, fractional shortening, cardiac output and stroke volume. Female mice were less susceptible to doxorubicin-induced cardiac damage and functional changes than males, but -deficient females had improved vacuolation with doxorubicin treatment. Sex differences were observed in wild-type and -deficient mice in body-weight and expression of and in response to doxorubicin. Trpc6 promotes cardiac damage following treatment with doxorubicin resulting in cardiomyopathy in male mice. Female mice are less susceptible to cardiotoxicity with more robust ability to modulate other Trpc channels and Rcan1 expression.

Citing Articles

Distinct Impact of Doxorubicin on Skeletal Muscle and Fat Metabolism in Mice: Without Dexrazoxane Effect.

Van Asbroeck B, Kruger D, Van den Bogaert S, Dombrecht D, Bosman M, Van Craenenbroeck E Int J Mol Sci. 2025; 26(3).

PMID: 39940943 PMC: 11818201. DOI: 10.3390/ijms26031177.


Brief Magnetic Field Exposure Stimulates Doxorubicin Uptake into Breast Cancer Cells in Association with TRPC1 Expression: A Precision Oncology Methodology to Enhance Chemotherapeutic Outcome.

Sukumar V, Tai Y, Chan C, Iversen J, Wu K, Fong C Cancers (Basel). 2024; 16(22).

PMID: 39594815 PMC: 11592624. DOI: 10.3390/cancers16223860.


Computational approaches identify a transcriptomic fingerprint of drug-induced structural cardiotoxicity.

Au Yeung V, Obrezanova O, Zhou J, Yang H, Bowen T, Ivanov D Cell Biol Toxicol. 2024; 40(1):50.

PMID: 38940987 PMC: 11213733. DOI: 10.1007/s10565-024-09880-7.


Research summary of poster presentations at the 2023 Florida cardio-oncology symposium.

Bruno K, ODell W, Tantawy M, Casson C, Ferrall-Fairbanks M, DeRemer D Am Heart J Plus. 2024; 37:100348.

PMID: 38510509 PMC: 10945887. DOI: 10.1016/j.ahjo.2023.100348.


[Platycodin D improves pulmonary fibrosis in mice by down-regulating TRPC6 expression and reducing ROS production in lung fibroblasts].

Liang Z, Yu C, Liang S, Zhou Z, Meng X, Zou F Nan Fang Yi Ke Da Xue Xue Bao. 2024; 44(1):60-69.

PMID: 38293977 PMC: 10878886. DOI: 10.12122/j.issn.1673-4254.2024.01.08.


References
1.
Suchyna T . Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology. Prog Biophys Mol Biol. 2017; 130(Pt B):244-253. PMC: 5716857. DOI: 10.1016/j.pbiomolbio.2017.07.011. View

2.
Simunek T, Sterba M, Popelova O, Adamcova M, Hrdina R, Gersl V . Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Rep. 2009; 61(1):154-71. DOI: 10.1016/s1734-1140(09)70018-0. View

3.
Jardin I, Diez-Bello R, Lopez J, Redondo P, Salido G, Smani T . TRPC6 Channels Are Required for Proliferation, Migration and Invasion of Breast Cancer Cell Lines by Modulation of Orai1 and Orai3 Surface Exposure. Cancers (Basel). 2018; 10(9). PMC: 6162527. DOI: 10.3390/cancers10090331. View

4.
Bien S, Riad A, Ritter C, Gratz M, Olshausen F, Westermann D . The endothelin receptor blocker bosentan inhibits doxorubicin-induced cardiomyopathy. Cancer Res. 2007; 67(21):10428-35. DOI: 10.1158/0008-5472.CAN-07-1344. View

5.
Chang A, Chang S, Garcia R, Schilling W . Concomitant and hormonally regulated expression of trp genes in bovine aortic endothelial cells. FEBS Lett. 1997; 415(3):335-40. DOI: 10.1016/s0014-5793(97)01155-1. View