Abstract
BackgroundSenescence 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. 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 ResultsSMP30 knockout (SMP30 KO) mice, SMP30 transgenic (SMP30 TG) mice with cardiac-specific overexpression of SMP30 gene and wild-type (WT) littermate mice at 12–14 weeks of age were given intra-peritoneal injection of DOX (20 mg/kg) or saline. Five 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 reactive oxygen species 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 numbers of deoxynucleotidyltransferase-mediated dUTP nick end-labeling positive nuclei in the myocardium, apoptotic signaling pathways such as caspase-3 activity, Bax/Bcl-2 ratio and phosphorylation activity of c-Jun N-terminal kinase were increased in SMP30 KO mice and decreased in SMP30 TG mice compared with WT mice after DOX injection.ConclusionsSMP30 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.
Highlights
[1] It has been known since the 1970s that anthracycline treatment is associated with an increased risk of heart failure, and that this is dependent on cumulative dose and schedule. [2,3] One of the mechanisms responsible for doxorubicin (DOX) cardiotoxicity is the formation of reactive oxygen species (ROS), [4,5] which can harm membrane lipids and other cellular components, leading to cardiomyocyte apoptosis and death
ejection fraction (EF) and fractional shortening (FS) were more severely reduced in the DOX-treated Senescence marker protein 30 (SMP30) KO mice compared with the DOX-treated WT mice (P,0.01 and P,0.05, respectively)
These echocardiographic data revealed that the left ventricular systolic function was depressed in the DOX-treated SMP30 KO mice compared with the DOX-treated WT mice
Summary
Anthracyclines are the drugs most closely related to acute and late cardiac toxicity. [1] It has been known since the 1970s that anthracycline treatment is associated with an increased risk of heart failure, and that this is dependent on cumulative dose and schedule. [2,3] One of the mechanisms responsible for doxorubicin (DOX) cardiotoxicity is the formation of reactive oxygen species (ROS), [4,5] which can harm membrane lipids and other cellular components, leading to cardiomyocyte apoptosis and death. [6] In addition, oxidative stress is considered to be an important factor of controlling heart aging. [7]Senescence marker protein 30 (SMP30), a 34-kDa protein, was originally identified as a novel aging marker protein in rat liver, whose expression decreases androgen-independently with age. [8] SMP30 transcripts are detected in almost all organs, and the SMP30 gene is highly conserved among numerous animal species including humans. [9] It has been demonstrated that SMP30 plays multifunctional roles as Ca2+ regulator, [10] anti-oxidants, [11] and gluconolactonase which is a key enzyme in the ascorbic acid (vitamin C) biosynthesis. [12] SMP30 knockout (SMP30 KO) mice were generated [13] and showed a shorter life span than that of wild-type (WT) mice on a vitamin C-deficient diet. [14] Using SMP30 KO mice, recent reports have demonstrated that SMP30 functions to protect cells from apoptosis in the liver [13] and that SMP30 has protective effects against age-associated oxidative stress in the brain [15] and lungs [16]. [14] Using SMP30 KO mice, recent reports have demonstrated that SMP30 functions to protect cells from apoptosis in the liver [13] and that SMP30 has protective effects against age-associated oxidative stress in the brain [15] and lungs [16]. We hypothesized that SMP30 has cardio-protective functions in response to DOX. To test this hypothesis, we generated transgenic mice with cardiac-specific over expression of SMP30 gene (SMP30 TG). 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. We hypothesized that SMP30 has cardio-protective function due to its anti-aging and anti-oxidant effects on doxorubicin (DOX)-induced cardiac dysfunction
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