Novel ASK1 inhibitor AGI‐1067 improves AGE‐induced cardiac dysfunction by inhibiting MKKs/p38 MAPK and NF‐κB apoptotic signaling

Abstract

Heart failure has been identified as one of the clinical manifestations of diabetic cardiovascular complications. Excessive myocardium apoptosis characterizes cardiac dysfunctions, which are correlated with an increased level of advanced glycation end products (AGEs). In this study, we investigated the participation of reactive oxygen species (ROS) and the involvements of apoptosis signal‐regulating kinase 1 (ASK1)/mitogen‐activated protein kinase (MAPK) kinases (MKKs)/p38 MAPK and nuclear factor κB (NF‐κB) pathways in AGE‐induced apoptosis‐mediated cardiac dysfunctions. The antioxidant and therapeutic effects of a novel ASK1 inhibitor, AGI‐1067, were also studied. Myocardium and isolated primary myocytes were exposed to AGEs and treated with AGI‐1067. Invasive hemodynamic and echocardiographic assessments were used to evaluate the cardiac functions. ROS formation was evaluated by dihydroethidium fluorescence staining. A terminal deoxynucleotidyl transferase dUTP nick end labelling assay was used to detect the apoptotic cells. ASK1 and NADPH activities were determined by kinase assays. The association between ASK1 and thioredoxin 1 (Trx1) was assessed by immunoprecipitation. Western blotting was used to evaluate the phosphorylation and expression levels of proteins. Our results showed that AGE exposure significantly activated ASK1/MKKs/p38 MAPK, which led to increased cardiac apoptosis and cardiac impairments. AGI‐1067 administration inhibited the activation of MKKs/p38 MAPK by inhibiting the disassociation of ASK1 and Trx1, which suppressed the AGE‐induced myocyte apoptosis. Moreover, the NF‐κB activation as well as the ROS generation was inhibited. As a result, cardiac functions were improved. Our findings suggested that AGI‐1067 recovered AGE‐induced cardiac dysfunction by blocking both ASK1/MKKs/p38 and NF‐κB apoptotic signaling pathways.

Keywords

• advanced glycation end products
• apoptosis
• apoptosis signal‐regulating kinase
• diabetes
• heart failure