Abstract 9362: Senescence Marker Protein 30 has a Cardio-protective Role in Doxorubicin-induced Cardiac Dysfunction

Abstract

Background: Senescence marker protein 30 (SMP30), which was originally identified as an aging marker protein, is assumed to act as a novel anti-aging factor in the liver, lungs and brain. Anthracyclines are the drugs most closely related to acute and late cardiac toxicity. One of the mechanisms responsible for doxorubicin (DOX) cardiotoxicity is the formation of reactive oxygen species (ROS) which can harm membrane lipids and other cellular components, leading to cardiomyocyte apoptosis and death. We hypothesized that SMP30 has cardio-protective function due to its anti-aging and anti-oxidant effects on doxorubicin (DOX)-induced cardiac dysfunction. Methods and Results: SMP30 knockout (SMP30 KO) mice, SMP30 transgenic (SMP30 TG) mice with cardiac-specific overexpression of SMP30 gene and wild-type (WT) littermate mice were given intra-peritoneal injections of DOX (20 mg/kg) or saline. Seven days after DOX injection, echocardiography revealed that left ventricular ejection fraction was more severely reduced in the DOX-treated SMP30 KO mice than in the DOX-treated WT mice, but was preserved in the DOX-treated SMP30 TG mice. Generation of ROS and oxidative DNA damage in the myocardium were greater in the DOX-treated SMP30 KO mice than in the DOX-treated WT mice, but much less in the SMP30 TG mice. The number of deoxynucleotidyl transferase-mediated dUTP nick end-labeling positive cardiomyocytes was higher in the DOX-treated SMP30 KO mice and lower in the DOX-treated SMP30 TG mice compared to that in the DOX-treated WT mice. Caspase-3 activity was higher in the DOX-treated SMP30 KO mice and lower in the DOX-treated SMP30 TG mice compared with the DOX-treated WT mice. The ratio of Bax to Bcl-2 was higher in the DOX-treated SMP30 KO mice and lower in the DOX-treated SMP30 TG mice than in the DOX-treated WT mice. Phosphorylation activity of SAPK/JNK was increased in the DOX-treated SMP30 KO mice and was decreased in the DOX-treated SMP30 TG mice compared with the DOX-treated WT mice. Conclusions: SMP30 has a cardio-protective role by anti-oxidative and anti-apoptotic effects in DOX-induced cardiotoxicity, and can be a new therapeutic target to prevent DOX-induced heart failure.