Rutin attenuates doxorubicin-induced cardiotoxicity via regulating autophagy and apoptosis

Abstract

Doxorubicin as anticancer agent can cause dose-dependent cardiotoxicity and heart failure in the long term. Rutin as a polyphenolic flavonoid has been illustrated to protect hearts from diverse cardiovascular diseases. Its function is known to be related to its antioxidant and antiinflammatory activity which may regulate multiple cellular signal pathways. However, the role of rutin on doxorubicin-induced cardiotoxicity has yet to be discovered. In this study, we explored the protective role of rutin on doxorubicin-induced heart failure and elucidated the potential mechanisms of protective effects of rutin against cardiomyocyte death. We analyzed cardiac tissues at the time point of 8weeks after doxorubicin treatment. The results by echocardiography, TUNEL staining, Masson's trichrome staining as well as Western blot analysis revealed that doxorubicin induced remarkable cardiac dysfunction and cardiotoxicity in mice hearts and cardiomyocytes, which were alleviated by rutin treatment. Western blot analysis indicated that the underlying mechanisms included inhibition excessive autophagy and apoptosis mediated by Akt activation. Collectively, our findings suggest that suppression of autophagy and apoptosis by administration of rutin could attenuate doxorubicin-induced cardiotoxicity, which enhances our knowledge to explore new drugs and strategies for combating this devastating side effect induced by doxorubicin. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang.

Cardiotoxic Effects of Short-Term Doxorubicin Administration: Involvement of Connexin 43 in Calcium Impairment

“…The exact pathogenesis of DOXO-induced cardiotoxicity is not fully understood even if it is assumed that it is multifactorial [ 9 , 10 , 11 , 12 ]. Several lines of evidence indicate that DOXO-induced cardiomyopathy is characterized by abnormal calcium homeostasis, but most of the studies published report only the effects of long-term DOXO-administration [ 13 , 14 , 15 , 16 ]. Recently, we have demonstrated that DOXO administration is able to induce calcium dysregulation and Connexin43 (Cx43) re-arrangement in a rat cardiomyoblast cell line already evident after a short-term administration [ 17 ].…”

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

“…Researchers have focused concentration on identifying small molecules acting as chaperones to stimulate or stabilize proteins that regulate autophagy [6]. There is evidence indicated that LPS can induce autophagy in macrophages and mice [7,8]. It was reported that cardiac-specific Atg5-defcient mice showed age-related cardiomyopathy.…”

TLR9 deficiency alleviates doxorubicin‐induced cardiotoxicity via the regulation of autophagy

“…Moreover, autophagy contributes to mitochondrial function maintenance, resulting in the alleviation of ROS accumulation and apoptosis upon DOX challenge 42,43 . However, autophagy may be promoted by low doses of DOX in cardiomyocytes; this is detrimental to cardiomyocyte survival 44‐46 . It has been reported that preventing autophagy, such as the silencing of beclin‐1 and activation of GATA4 and AKT have been shown to be protective against cardiac cells exposed to DOX 44,45,47 .…”