MicroRNA‐210 repression facilitates advanced glycation end‐product (AGE)‐induced cardiac mitochondrial dysfunction and apoptosis via JNK activation

Abstract

Hyperglycemia results in the formation of reactive oxygen species which in turn causes advanced glycation end products (AGEs) formation, leading to diabetic cardiomyopathy. Our previous study showed that AGE‐induced reactive oxygen species‐dependent apoptosis is mediated via protein kinase C delta (PKCδ)‐enhanced mitochondrial damage in cardiomyocytes. By using microRNA (miRNA) database, miRNA‐210 was predicted to target c‐Jun N‐terminal kinase (JNK), which were previously identified as downstream of PKCδ in regulating mitochondrial function. Therefore, we hypothesized that miR‐210 mediates PKCδ‐dependent upregulation of JNK to cause cardiac mitochondrial damage and apoptosis following AGE exposure. AGE‐exposed cells showed activated cardiac JNK, PKCδ, and apoptosis, which were reversed by treatment with a JNK inhibitor and PKCδ‐KD (deficient kinase). Cardiac miR‐210 and mitochondrial function were downregulated following AGE exposure. Furthermore, JNK was upregulated and involved in AGE‐induced mitochondrial damage. Interestingly, luciferase activity of the miR‐210 mimic plus JNK WT‐3′‐untranslated region overexpressed group was significantly lower than that of miR‐210 mimic plus JNK MT‐3′UTR group, indicating that JNK is a target of miR‐210. Moreover, JNK activation induced by AGEs was reduced by treatment with the miR‐210 mimic and reversed by treatment with the miR‐210 inhibitor, indicating the regulatory function of miR‐210 in JNK activation following AGE exposure. Additionally, JNK‐dependent mitochondrial dysfunction and apoptosis were reversed following treatment with the miR‐210 mimic, while the miR‐210 inhibitor showed no effect on JNK‐induced mitochondrial dysfunction and apoptosis in AGE‐exposed cardiac cells. Taken together, our study showed that PKCδ‐enhanced JNK‐dependent mitochondrial damage is mediated through the reduction of miR‐210 in cardiomyocytes following AGE exposure.

Emerging roles of microRNAs as diagnostics and potential therapeutic interest in type 2 diabetes mellitus

“…miR-210 downregulation plays a protective role in T2DM by regulating endothelial function. MiR-210 also mitigates AGE-mediated activation of JNK (c-Jun N-terminal kinase) and PKC, reversing pathological conditions in cardiomyocytes[ 54 ]. MiR-25 regulates the AGE/RAGE-activated PKC pathway in diabetic nephropathy, inhibiting PKC phosphorylation and reducing oxidative stress[ 55 ].…”

“…miRNAs' expression in metabolic disease and reported therapeutic approaches are given in Table 3 . Lin et al [ 54 ] suggested the therapeutic role of miR-210 in AGEs-exposed cardiomyocytes by using a miR-210 mimic and hypothesised that downregulation of miR-210 in AGEs-induced cardiomyocytes would reduce PKC-enhanced JNK-dependent mitochondrial damage. Chen et al [ 71 ] suggested that downregulation of miR-29b plays a role in the development of diabetic nephropathy.…”

Involvement of Mitochondrial Dysfunction in the Inflammatory Response in Human Mesothelial Cells from Peritoneal Dialysis Effluent

“…This anti-inflammatory effect is mediated by decreased NF-κB activation. In relation to this, the ways in which resveratrol attenuates advanced glycation end product (AGE)-induced damage in human peritoneal mesothelial cells [ 65 ] have recently been described, which could potentially lead to mitochondrial damage [ 66 ]. Taken together, these data underline the relevance of our findings regarding the beneficial effects of resveratrol to preserve mitochondrial function in mesothelial cells in patients undergoing PD treatment.…”

Activation of PI3K/Akt mediates the protective effect of diallyl trisulfide on doxorubicin induced cardiac apoptosis

“…DAPI staining and TUNEL (terminal deoxynucleotide transferase-mediated dUTP nick end labeling) assay were performed following previously described methods, utilizing an In Situ Cell Death Detection Kit (Roche) ( Lin et al, 2021 ). Cultured cells were fixed with a 4 % paraformaldehyde solution for 30 min at room temperature, followed by PBS washing and permeabilization with a solution containing 0.1 % Triton X-100 in 0.1 % sodium citrate for 2 min.…”