Mondal Arunima, Das Shreya, Samanta Jayeeta, Chakraborty Santanu, Sengupta Arunima
Department of Life Science and Biotechnology, Jadavpur University, Kolkata, India.
Department of Life Sciences, Presidency University, Kolkata, India.
Arch Biochem Biophys. 2022 Jun 15;722:109198. doi: 10.1016/j.abb.2022.109198. Epub 2022 Mar 28.
Cardiac disease is one of the most common complications associated with diabetes. Cardiac hypertrophy and fibrosis often lead to structural and functional abnormalities leading to risks of heart failure. Several regulatory molecules related to major signaling pathways have been found to overexpress in different tissues during diabetes which show very low level of expression in non-diabetic condition. YAP1 and FOXM1 are recently being reported to play important role in various hypertrophic and fibrotic disorders. But, very limited information is still known regarding their roles in cardiomyopathies especially in the context of diabetes and hyperglycemic stress. YAP1 is known to be associated with AKT- GSK3β signaling that is one of the important regulatory pathways in glucose and lipid metabolism. On the other hand, the expression of FOXM1 has been found to be significantly upregulated in adult lung tissue with induction of fibrosis but little is known about their role in cardiac diseases. In our study, YAP1 and FOXM1 have been found to overexpress in cardiac tissue under hyperglycemic condition leading to cardiomyocyte hypertrophy and increased fibrotic response. Further YAP1 inhibition has resulted in a reduced expression of FOXM1 pointing to a possible association of YAP1 and FOXM1 in high glucose-stressed cardiomyocyte. As mechanism we have found that YAP1 undergoes reduced ser127 phosphorylation as well as extensive O-GlcNAcylation mediated activation under hyperglycemia. Upregulated YAP1 further acts through increased AKT phosphorylation causing inhibition of GSK3β that in turn results in increased FOXM1 expression, leading to cardiomyocyte hypertrophy and fibrosis.
心脏病是糖尿病最常见的并发症之一。心脏肥大和纤维化常导致结构和功能异常，进而引发心力衰竭风险。已发现与主要信号通路相关的几种调节分子在糖尿病期间于不同组织中过度表达，而在非糖尿病状态下其表达水平极低。YAP1和FOXM1最近被报道在各种肥大和纤维化疾病中发挥重要作用。但是，关于它们在心肌病中的作用，尤其是在糖尿病和高血糖应激背景下的作用，所知信息仍然非常有限。已知YAP1与AKT - GSK3β信号通路相关，该信号通路是葡萄糖和脂质代谢的重要调节途径之一。另一方面，已发现FOXM1在成年肺组织纤维化诱导时表达显著上调，但对其在心脏病中的作用知之甚少。在我们的研究中，发现YAP1和FOXM1在高血糖条件下于心脏组织中过度表达，导致心肌细胞肥大和纤维化反应增加。进一步抑制YAP1导致FOXM1表达降低，这表明YAP1和FOXM1在高糖应激心肌细胞中可能存在关联。作为机制，我们发现YAP1在高血糖状态下ser127磷酸化减少以及O - GlcNAcylation介导的广泛激活。上调的YAP1进一步通过增加AKT磷酸化发挥作用，导致GSK3β抑制，进而导致FOXM1表达增加，从而导致心肌细胞肥大和纤维化。
