Cardiac-specific LUZP1 overexpression attenuated doxorubicin-induced inflammation, oxidative damage, cell apoptosis, and cardiac injury in mice by activating the AMPK pathway.
Does LUZP1 overexpression prevent doxorubicin-induced cardiotoxicity in mice?
LUZP1 overexpression protects against doxorubicin-induced cardiotoxicity in mice by activating the AMPK pathway, suggesting a potential therapeutic target.
OBJECTIVE: Doxorubicin (DOX) is commonly used for chemotherapy; however, its clinical value is extremely dampened because of the fatal cardiotoxicity. Leucine zipper protein 1 (LUZP1) plays critical roles in cardiovascular development, and this study is designed for determining its function and mechanism in DOX-induced cardiotoxicity. METHODS: Cardiac-specific Luzp1 knockout (cKO) and transgenic (cTG) mice received a single or repeated DOX injections to establish acute and chronic cardiotoxicity. Biomarkers of inflammation, oxidative damage and cell apoptosis were evaluated. Transcriptome and co-immunoprecipitation analysis were used to screen the underlying molecular pathways. Meanwhile, primary cardiomyocytes were applied to confirm the beneficial effects of LUZP1 in depth. RESULTS: LUZP1 was upregulated in DOX-injured hearts and cardiomyocytes. Cardiac-specific LUZP1 deficiency aggravated, while cardiac-specific LUZP1 overexpression attenuated DOX-associated inflammation, oxidative damage, cell apoptosis and acute cardiac injury. Mechanistic studies revealed that LUZP1 ameliorated DOX-induced cardiotoxicity through activating 5'-AMP-activated protein kinase (AMPK) pathway, and AMPK deficiency abolished the cardioprotection of LUZP1. Further findings suggested that LUZP1 interacted with protein phosphatase 1 to activate AMPK pathway. Moreover, we determined that cardiac-specific LUZP1 overexpression could also attenuate DOX-associated chronic cardiac injury in mice. CONCLUSION: LUZP1 attenuates DOX-induced inflammation, oxidative damage, cell apoptosis and ventricular impairment through regulating AMPK pathway, and gene therapy targeting LUZP1 may provide novel therapeutic approached to treat DOX-induced cardiotoxicity.
Fan et al. (Sun,) conducted a other in Doxorubicin-induced cardiotoxicity. LUZP1 genetic manipulation (knockout or overexpression) was evaluated on Inflammation, oxidative damage, cell apoptosis, and cardiac injury. Cardiac-specific LUZP1 overexpression attenuated doxorubicin-induced inflammation, oxidative damage, cell apoptosis, and cardiac injury in mice by activating the AMPK pathway.