Abstract
Cardiovascular disease (CVD) is a lifestyle-related disease (LSRD) and one of the largest public health issues. Risk factors for CVD correlate with an excessive intake of glucose and/or fructose, which has been shown to induce the production of advanced glycation end-products (AGEs). We previously identified AGEs derived from glyceraldehyde and named them toxic AGEs (TAGE) due to their cytotoxicities and relationship with LSRD. We also reported that extracellular TAGE in the vascular system may promote CVD and that serum TAGE levels are associated with risk factors for CVD. The mechanisms responsible for the onset and/or progression of CVD by extracellular TAGE or the above risk factors involve vascular disorders. In the present study, we revealed that rat primary cultured cardiomyocytes generated intracellular TAGE, which decreased beating rates and induced cell death. LC3-II/LC3-I, a factor of autophagy, also decreased. Although intracellular TAGE may be targets of degradation as cytotoxic proteins via autophagy, they may inhibit autophagy. Furthermore, the mechanisms by which intracellular TAGE decrease beating rates and induce cell death may involve the suppression of autophagy. The present results suggest that intracellular TAGE are generated in cardiomyocytes and directly damage them, resulting in CVD.
Highlights
Cardiovascular disease (CVD) is a lifestyle-related disease (LSRD) and one of the largest public health issues of this century
We previously reported that the activation of the extracellular toxic AGEs (TAGE) receptor for advanced glycation end-products (AGEs) (RAGE) axis resulted in the generation of intracellular reactive oxygen species and the subsequent activation of nuclear factor-κB in vascular wall cells, which may promote the expression of various atherosclerosis- and inflammation-related genes, thereby contributing to the onset and/or progression of CVD in DM1
Our findings indicated that serum TAGE levels positively correlated with risk factors for CVD, including plasminogen activator inhibitor-121, fibrinogen[21], vascular inflammation[22], endothelial progenitor cells[23], plaque progression[24], the mean amplitude of glycemic excursions[25], asymmetric dimethylarginine[26], trimethylamine[27], and the cardio-ankle vascular index[28], in patients with LSRD, and in healthy humans
Summary
Cardiovascular disease (CVD) is a lifestyle-related disease (LSRD) and one of the largest public health issues of this century. The mechanisms by which extracellular TAGE or the above risk factors promote CVD involve vascular disorders. It currently remains unclear whether intracellular TAGE are generated in cardiac cells. If our hypothesis is correct, intracellular TAGE in cardiac cells may cause damage, resulting in CVD without vascular disorders. We considered it important to investigate the generation of TAGE in cardiomyocytes because the beating rate is a very important and characteristic function of cardiac cells[33,34,35,36]. We analyzed LC3-II/LC3-I and p62, which are factors of autophagy
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