Abstract
Doxorubicin (DOX), a chemotherapeutic drug widely used in the clinical setting, is known to cause serious cardiotoxicity and greatly reduces the survival rate as well as quality of life of patients receiving chemotherapy. Peroxisome proliferation activated receptor α (PPARα) is a type of ligand activated receptor of the nuclear hormone receptor family that regulates multiple gene expression. Several studies have shown that PPARα has anti-apoptotic and cardio-protective effects. However, its role in DOX-induced cardiotoxicity is rarely reported. In this study, we observed decreased expression of PPARα in the heart of tumor-bearing mice already treated with DOX; however, no such phenomenon was observed in tumor tissues. Next, we observed that the PPARα agonist, fenofibrate (FENO), had no effect on tumor progression; however, it enhanced cardiac function in tumor-bearing mice treated with DOX. Subsequently, recombinant adeno-associated virus serotype 9 (rAAV9) was used to manipulate the expression of PPARα in the heart of DOX-induced mice. Our results showed that PPARα gene delivery reduced cardiac dysfunction and mitochondria-dependent apoptosis in DOX-induced mice. Furthermore, we found that PPARα directly regulated the expression of mesenchyme homeobox 1 (MEOX1). Most importantly, the cardioprotective effects of PPARα could be neutralized by knocking down MEOX1. In summary, PPARα plays a vital role in DOX-induced cardiotoxicity and is a promising treatment target.
Highlights
Doxorubicin (DOX), originally obtained from Streptomyces mutants, is a widely used chemotherapeutic drug
The present study show that Peroxisome proliferation activated receptor a (PPARa) can upregulate the expression of mesenchyme homeobox 1 (MEOX1), thereby ameliorating mitochondrial function deteriorated by DOX, and reducing mitochondria-dependent apoptosis (Figure 8)
These findings suggest that MEOX1 might be an additional protective target of PPARa
Summary
Doxorubicin (DOX), originally obtained from Streptomyces mutants, is a widely used chemotherapeutic drug. It has a high affinity for DNA and forms DOX-DNA complexes, resulting in mitotic disorder and DNA double strand breakage (Renu et al, 2018). One of the most serious complications of DOX is cardiomyopathy, which occurs in patients 4 to 20 years after DOX treatment, with varying degrees of concentration dependence (Singal and Iliskovic, 1998). This property is called as “dose memory.”. The mechanism of DOX-induced cardiotoxicity is very complex and requires further investigation
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