Bone marrow mesenchymal stem cells inhibit cardiac hypertrophy by enhancing FoxO1 transcription

Abstract

Bone marrow–derived mesenchymal stem cells (BMSCs) have therapeutic potential for certain heart diseases. Previous studies have shown that stem cells inhibit cardiac hypertrophy; however, it is necessary to explore the mechanisms underlying this effect. This study aimed to investigate the possible mechanism underlying the inhibitory effect of BMSCs on cardiomyocyte hypertrophy. We induced cardiomyocyte hypertrophy in cultured rat cells through isoproterenol (ISO) treatment with or without BMSC coculture. A microarray was performed to analyze messenger RNA expression in response to ISO treatment and BMSC coculture. Pathway enrichment analysis showed that the expression of differential genes was closely related to the 5′‐adenosine monophosphate‐activated protein kinase (AMPK) signaling pathway and that the expression of forkhead box O 1 (FoxO1) was significantly increased in the presence of BMSCs. Furthermore, we determined the expression levels of p‐AMPK/AMPK and p‐FoxO1/FoxO1 by western blot analysis. The expression of p‐AMPK/AMPK was upregulated, whereas that of p‐FoxO1/FoxO1 was downregulated upon coculturing with BMSCs. The AMPK‐specific antagonist Compound C inhibited the downregulation of p‐FoxO1/FoxO1 induced by the BMSC coculture. Furthermore, treatment with the specific FoxO1 antagonist AS1842856 reduced the inhibitory effects of BMSCs on cardiomyocyte hypertrophy in vivo and in vitro. Our present study demonstrates the inhibition of cardiomyocyte hypertrophy by BMSCs, which occurs partly through the AMPK–FoxO1 signaling pathway.

Parishin alleviates vascular ageing in mice by upregulation of Klotho

“…Subcellular localization and transcriptional activity of FoxO1 are regulated by post‐translational modifications (e.g. phosphorylation), which inhibit FoxO1 by inducing cytoplasmic localization and proteasomal degradation activity of FoxO1 48 . FoxO1 in the nucleus directly binds to the promoter of the antioxidant stress enzyme and exerts antioxidant effects 49 .…”

“…phosphorylation), which inhibit FoxO1 by inducing cytoplasmic localization and proteasomal degradation activity of FoxO1. 48 FoxO1 in the nucleus directly binds to the promoter of the antioxidant stress enzyme and exerts antioxidant effects. 49 In this study, both cellular and animal experiments showed that parishin intervention group was higher protein level of Klotho and FoxO1 than the control group (Figures 4 and 5 ).…”

Bone marrow mesenchymal stem cells-derived exosomal miR-185-5p plays a protective role in high-glucose stimulated human retinal microvascular endothelial cells in vitro by regulating CXCL8

“…As a type of pluripotent stem cells, BM-MSCs are capable of multi-differentiation and self-renewal. A number of reports have pointed out that BM-MSCs play a role in many diseases, such as kidney disease (24), osteogenesis induction and bone repair (25), tumors (26), rheumatoid arthritis (27), and heart-related diseases (28). In addition, it has been documented that BM-MSCs play a protective role in DR. Zhao H et al have manifested that BM-MSCs can inhibit the progression of DR by inhibiting oxidative stress and inflammatory pathways (29).…”

Diverse roles of FOXO family members in gastric cancer

“…Lu et al [ 40 ] proposed FO1–6nls, a FOXO1-derived peptide inhibitor of CDK1/2-mediated phosphorylation of FOXO1 at serine 249, as a potential therapeutic for the treatment of prostate cancers. AMPK phosphorylates FOXO1 and forms the AMPK/ FOXO1 axis, which is involved in multiple pathological processes, such as liver fibrosis[ 41 ], cardiac hypertrophy[ 42 ], and epithelial-mesenchymal transition (EMT)[ 43 ]. The phosphorylation of FOXO3 at serine 644 by IκK normally leads to ubiquitin-dependent proteasomal degradation[ 44 ], but causes cytoplasmic retention in acute myeloid leukemia[ 45 ].…”