Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China.
Department of Endocrine, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, 214125, China.
Cell Mol Biol Lett. 2023 Nov 22;28(1):93. doi: 10.1186/s11658-023-00510-4.
Periostin is an extracellular matrix protein that plays a critical role in cell fate determination and tissue remodeling, but the underlying role and mechanism of periostin in diabetic cardiomyopathy (DCM) are far from clear. Thus, we aimed to clarify the mechanistic participation of periostin in DCM.
The expression of periostin was examined in DCM patients, diabetic mice and high glucose (HG)-exposed cardiac fibroblasts (CF). Gain- and loss-of-function experiments assessed the potential role of periostin in DCM pathogenesis. RNA sequencing was used to investigate the underlying mechanisms of periostin in DCM.
A mouse cytokine antibody array showed that the protein expression of periostin was most significantly upregulated in diabetic mouse heart, and this increase was also observed in patients with DCM or HG-incubated CF. Periostin-deficient mice were protected from diabetes-induced cardiac dysfunction and myocardial damage, while overexpression of periostin held the opposite effects. Hyperglycemia stimulated the expression of periostin in a TGF-β/Smad-dependent manner. RNA sequencing results showed that periostin upregulated the expression of nucleosome assembly protein 1-like 2 (NAP1L2) which recruited SIRT3 to deacetylate H3K27ac on the promoters of the branched-chain amino acid (BCAA) catabolism-related enzymes BCAT2 and PP2Cm, resulting in BCAA catabolism impairment. Additionally, CF-derived periostin induced hypertrophy, oxidative injury and inflammation in primary cardiomyocytes. Finally, we identified that glucosyringic acid (GA) specifically targeted and inhibited periostin to ameliorate DCM.
Overall, manipulating periostin expression may function as a promising strategy in the treatment of DCM.
骨膜蛋白是一种细胞外基质蛋白，在细胞命运决定和组织重塑中起着关键作用，但骨膜蛋白在糖尿病心肌病（DCM）中的潜在作用和机制还远不清楚。因此，我们旨在阐明骨膜蛋白在 DCM 中的作用机制。
检测了 DCM 患者、糖尿病小鼠和高糖（HG）暴露的心肌成纤维细胞（CF）中骨膜蛋白的表达。通过增益和缺失功能实验评估了骨膜蛋白在 DCM 发病机制中的潜在作用。利用 RNA 测序研究了骨膜蛋白在 DCM 中的潜在机制。
小鼠细胞因子抗体阵列显示，糖尿病小鼠心脏中骨膜蛋白的蛋白表达显著上调，DCM 患者或 HG 孵育的 CF 中也观察到这种增加。骨膜蛋白缺陷小鼠免受糖尿病引起的心脏功能障碍和心肌损伤的影响，而过表达骨膜蛋白则产生相反的效果。高血糖以 TGF-β/Smad 依赖的方式刺激骨膜蛋白的表达。RNA 测序结果显示，骨膜蛋白上调核小体组装蛋白 1 样 2（NAP1L2）的表达，NAP1L2 募集 SIRT3 去乙酰化 H3K27ac 在支链氨基酸（BCAA）分解代谢相关酶 BCAT2 和 PP2Cm 的启动子上，导致 BCAA 分解代谢受损。此外，CF 来源的骨膜蛋白诱导原代心肌细胞肥大、氧化损伤和炎症。最后，我们确定了葡萄糖基丁香酸（GA）特异性靶向和抑制骨膜蛋白以改善 DCM。
总之，操纵骨膜蛋白的表达可能是治疗 DCM 的一种有前途的策略。
