Gab1 overexpression alleviates doxorubicin-induced cardiac oxidative stress, inflammation, and apoptosis through PI3K/Akt signaling pathway

Grb2-associated binding protein 1 (Gab1), an intracellular scaffolding adaptor, was involved in several cardiovascular diseases. However, the role of Gab1 in doxorubicin (DOX)-induced cardiotoxicity remains largely unknown. The present study investigated whether Gab1 protected against DOX-induced cardiotoxicity and the underlying mechanism. We overexpressed Gab1 in the hearts using an adeno-associated virus 9 system through tail vein injection. C57BL/6 mice were subjected to DOX (15 mg/kg/d, i.p.) to generate DOX-induced cardiotoxicity. Echocardiography, histological analysis, immunofluorescence and enzyme-linked immunosorbent assay (ELISA) kits, Western blotting, and quantitative real-time polymerase chain reaction (PCR) evaluated DOX-induced cardiotoxicity and the underlying mechanisms. Myocardial Gab1 protein and messenger RNA (mRNA) levels were markedly decreased in DOX-administered mice. Overexpression of Gab1 in myocardium significantly improved cardiac function and attenuated cardiac oxidative stress, inflammatory response, and apoptosis induced by DOX. Mechanistically, we found that PI3K/Akt signaling pathway was downregulated after DOX treatment, and Gab1 overexpression activated PI3K/Akt signaling pathway, whereas PI3K/Akt signaling pathway inhibition abolished the beneficial effect of Gab1 overexpression in the heart. Collectively, our results indicated that Gab1 is essential for cardioprotection against DOX-induced oxidative stress, inflammatory response, and apoptosis by mediating PI3K/Akt signaling pathway. And cardiac gene therapy with Gab1 provides a novel therapeutic strategy against DOX-induced cardiotoxicity.