ABSTRACT
Doxorubicin (DOX) possesses strong anti-tumor effects but is limited by its irreversible cardiac toxicity. The relationship between exercise, a known enhancer of cardiovascular health, and DOX-induced cardiotoxicity has been a focus of recent research. Exercise has been suggested to mitigate DOX's cardiac harm by modulating the Yes-associated protein (YAP) and Signal transducer and activator of transcription 3 (STAT3) pathways, which are crucial in regulating cardiac cell functions and responses to damage. This study aimed to assess the protective role of exercise preconditioning against DOX-induced cardiac injury. We used Sprague-Dawley rats, divided into five groups (control, DOX, exercise preconditioning (EP), EP-DOX, and verteporfin + EP + DOX), to investigate the potential mechanisms. Our findings, including echocardiography, histological staining, Western blot, and q-PCR analysis, demonstrated that exercise preconditioning could alleviate DOX-induced cardiac dysfunction and structural damage. Notably, exercise preconditioning enhanced the nuclear localization and co-localization of YAP and STAT3. Our study suggests that exercise preconditioning may counteract DOX-induced cardiotoxicity by activating the YAP/STAT3 pathway, highlighting a potential therapeutic approach for reducing DOX's cardiac side effects.
ABSTRACT
The transcriptional co-activator Yes-associated protein (YAP) functions as a downstream effector of the Hippo signaling pathway and plays a crucial role in cardiomyocyte survival. In its non-phosphorylated activated state, YAP binds to transcription factors, activating the transcription of downstream target genes. It also regulates cell proliferation and survival by selectively binding to enhancers and activating target genes. However, the upregulation of the Hippo pathway in human heart failure inhibits cardiac regeneration and disrupts astrogenesis, thus preventing the nuclear translocation of YAP. Existing literature indicates that the Hippo/YAP axis contributes to inflammation and fibrosis, potentially playing a role in the development of cardiac, vascular and renal injuries. Moreover, it is a key mediator of myofibroblast differentiation and fibrosis in the infarcted heart. Given these insights, can we harness YAP's regenerative potential in a targeted manner? In this review, we provide a detailed discussion of the Hippo signaling pathway and consolidate concepts for the development and intervention of cardiac anti-aging drugs to leverage YAP signaling as a pivotal target.
