Abstract
The transient receptor potential ankyrin 1 (TRPA1) channel is expressed in cardiomyocytes and involved in many cardiovascular diseases. However, the expression and function of TRPA1 in doxorubicin- (Dox-) induced acute cardiotoxicity have not been elucidated. This study aimed at investigating whether blocking the TRPA1 channel with the specific inhibitor HC-030031 (HC) attenuates Dox-induced cardiac injury. The animals were randomly divided into four groups: control, HC, Dox, and Dox + HC. Echocardiography was used to evaluate cardiac function, and the heart was removed for molecular experiments. The results showed that the expression of TRPA1 was increased in the heart after Dox treatment. Cardiac dysfunction and increased serum CK-MB and LDH levels were induced by Dox, but these effects were attenuated by HC treatment. In addition, HC mitigated Dox-induced oxidative stress, as evidenced by the decreased MDA level and increased GSH level and SOD activity in the Dox + HC group. Meanwhile, HC treatment lowered the levels of the proinflammatory cytokines IL-1β, IL-6, IL-17, and TNF-α induced by Dox. Furthermore, HC treatment mitigated endoplasmic reticulum (ER) stress and cardiomyocyte apoptosis induced by Dox. These results indicated that inhibition of TRPA1 could prevent Dox-induced cardiomyocyte apoptosis in mice by inhibiting oxidative stress, inflammation, and ER stress.
Highlights
Doxorubicin (Dox), an anthracycline anticancer drug, is one of the most preferred agents for the treatment of different malignant tumors, including leukemia, lymphomas, breast cancer, and ovarian cancer
We clearly show that the inhibition of transient receptor potential ankyrin 1 (TRPA1) ameliorated Dox-induced cardiomyocyte apoptosis and cardiac dysfunction, which correlated with decreases in oxidative stress products, proinflammatory cytokine levels, and endoplasmic reticulum (ER) stress
These results suggested that TRPA1 expression is induced by Dox treatment and that TRPA1 may be involved in Dox-induced cardiotoxicity
Summary
Doxorubicin (Dox), an anthracycline anticancer drug, is one of the most preferred agents for the treatment of different malignant tumors, including leukemia, lymphomas, breast cancer, and ovarian cancer. Its application is hampered due to a significant dose-dependent cardiotoxicity manifested by cardiomyopathy and congestive heart failure [1, 2]. A recent study reported that 21% of patients developed chemotherapy-related cardiotoxicity after Dox administration [3]. Transient receptor potential (TRP) channels are nonselective cation channels that mediate sensory transduction and respond to various stimuli. The 28 mammalian TRP channels can be grouped into six subfamilies based on sequence homology. TRPA1 is predominantly expressed in nociceptive neurons and is expressed at high levels in the heart, lung, skeletal muscle, skin, and vascular endothelial cells [4, 5]. Takahashi et al demonstrated that TRPA1 directly detects molecular oxygen and plays a pivotal role in maintaining oxygen homeostasis [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
