Abstract
Doxorubicin- (DOX-) induced cardiomyocyte loss results in irreversible heart failure, which limits the clinical applications of DOX. Currently, there are no drugs that can effectively treat DOX-related cardiotoxicity. Follistatin-like 1 (FSTL1) has been reported to be a transforming growth factor-beta-inducible gene, and FSTL1 supplementation attenuated ischemic injury and cardiac apoptotic loss in mice. However, the effect of FSTL1 on DOX-induced cardiomyopathy has not been elucidated. We aimed to explore whether FSTL1 could prevent DOX-related cardiotoxicity in mice. Mice were intraperitoneally injected with a single dose of DOX to induce acute cardiotoxicity. We used an adeno-associated virus system to overexpress FSTL1 in the heart. DOX administration decreased FSTL1 mRNA and protein expression in the heart and in cells. FSTL1 prevented DOX-related cardiac injury and inhibited cardiac oxidative stress and apoptosis, thereby improving cardiac function in mice. FSTL1 also improved cardiomyocyte contractile functions in vitro. FSTL1 upregulated expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in DOX-treated hearts. FSTL1 was not capable of protecting against these toxic effects in Nrf2-deficient mice. In conclusion, FSTL1 protected against DOX-induced cardiotoxicity via upregulation of Nrf2 expression.
Highlights
Doxorubicin (DOX), a well-known and highly effective chemotherapy drug, can contribute to the development of cardiotoxicity and irreversible heart failure, which largely limits its clinical use [1]
We showed for the first time that Follistatin-like 1 (FSTL1) expression was decreased in DOX-treated hearts and that FSTL1 overexpression prevented acute DOX-induced injury in the heart
We found that FSTL1 overexpression prevented DOX-related cardiac atrophy, oxidative damage, and apoptosis, improving cardiac function
Summary
Doxorubicin (DOX), a well-known and highly effective chemotherapy drug, can contribute to the development of cardiotoxicity and irreversible heart failure, which largely limits its clinical use [1]. The precise pathogenesis of DOX-related cardiotoxicity has not been completely elucidated, but several lines of evidence have suggested that oxidative damage and myocardial apoptotic loss are closely involved [3, 4]. Finding a drug that can restrict DOX-induced cardiac apoptosis might be important in treating DOX-related cardiac injury. It has been reported that FSTL1 supplementation limits ischemic injury and cardiac apoptotic loss in mice [5]. FSTL1 has been found to upregulate protein kinase B (PKB/AKT) activity in mice [5]. There have been no reports describing the role of FSTL1 in DOX-related acute cardiotoxicity
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