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

Abstract

Background: 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 TRPC6 have been associated with the development of doxorubicin-induced cardiotoxicity, suggesting that TRPC6 may be a therapeutic target for cardioprotection in cancer patients.Methods: Assessment of Trpc6 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 Tnni3 and Myh7. Cardiac function was determined by echocardiography.Results: When treated with doxorubicin, male Trpc6-deficient mice showed improvement in markers of cardiac damage with significantly reduced vacuolation, fibrosis and Myh7 expression and increased Tnni3 expression in the heart compared to wild-type controls. Similarly, male Trpc6-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 Trpc6-deficient females had improved vacuolation with doxorubicin treatment. Sex differences were observed in wild-type and Trpc6-deficient mice in body-weight and expression of Trpc1, Trpc3 and Rcan1 in response to doxorubicin.Conclusions: 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.

Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice

“…The heart weight (HW) to tibia length (TL) ratio (HW/TL) is most frequently used to indicate cardiac hypertrophy, but loss of heart weight can also indicate cardiac damage, as often occurs during viral myocarditis and other forms of cardiomyopathy. [ 60–62 ] Mice with viral myocarditis treated with PBS (control) had significantly lower heart weights than innate PEV‐treated mice ( p = 0.0005) at day 10 pi (Figure 4d). Normalized to the TL (Figure 4e), the HW/TL was significantly higher in mice with myocarditis treated with PEV than PBS (control)‐treated mice ( p = 0.0014) (Figure 4f) indicating that PEV protected the heart from cardiac damage during myocarditis.…”

Replication of genetic associations of chemotherapy-related cardiotoxicity in the adjuvant NSABP B-31 clinical trial

“…Firstly, TRPC6 is a non-selective calcium channel known to be involved in heart failure in general and in cardiac remodeling in animal models (19), and in our previous studies, TRPC6 knockout (21) and pharmacological inhibition of TRPC6 in vitro and in wildtype mice (20) attenuated doxorubicin-induced cardiotoxicity, respectively. Furthermore, a study by Kuwahara et al showed that TRPC6 was upregulated in mouse hearts subjected to pressure overload and in failing human hearts (19) and transcriptome-wide analysis (TWAS) of the GTEX tissues from heart left ventricle and decline in LVEF in the N9831 GWAS dataset demonstrated an association with TRPC6 (20).…”

“…Firstly, TRPC6 is a non-selective calcium channel known to be involved in heart failure in general and in cardiac remodeling in animal models ( 19 ), and in our previous studies, TRPC6 knockout ( 21 ) and pharmacological inhibition of TRPC6 in vitro and in wild-type mice ( 20 ) attenuated doxorubicin-induced cardiotoxicity, respectively. Furthermore, a study by Kuwahara et al.…”

Potential role of the apelin‐APJ pathway in sex‐related differential cardiotoxicity induced by doxorubicin in mice

“…Recently, the contribution of Transient Receptor Potential Canonical (TRPC) channel 6 to sex differences in DOX‐induced cardiotoxicity was explored in a Trpc6 ‐deficient mouse model (Norton et al, 2021). TRPC channels are a group of calcium permeable ion channels that play a significant role in pathological cardiac remodeling (Numaga‐Tomita & Nishida, 2020).…”

“…However, these DOX‐induced pathological changes were diminished, and cardiac function was improved, in male B6.129 Trpc6 whole body knock‐out mice, suggesting the role of Trpc6 in promoting cardiac damage after DOX treatment. In female mice, however, vacuolization was less severe than males in both wild‐type and Trpc6 ‐deficient mice and did not show any evidence of fibrosis or altered echocardiographic measures in response to DOX or a lack of Trpc6 (Norton et al, 2021).…”