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.

中文翻译：

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心脏成纤维细胞 BCAA 分解代谢紊乱通过骨膜素/NAP1L2/SIRT3 轴导致糖尿病心肌病

骨膜素是一种细胞外基质蛋白，在细胞命运决定和组织重塑中发挥着关键作用，但骨膜素在糖尿病心肌病（DCM）中的潜在作用和机制尚不清楚。因此，我们的目的是阐明骨膜素在扩张型心肌病中的参与机制。在 DCM 患者、糖尿病小鼠和高糖 (HG) 暴露的心脏成纤维细胞 (CF) 中检查了骨膜素的表达。功能获得和丧失实验评估了骨膜素在 DCM 发病机制中的潜在作用。RNA 测序用于研究骨膜素在 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素的蛋白表达最显着上调，并且在 DCM 或 HG 孵育的 CF 患者中也观察到这种增加。缺乏骨膜素的小鼠可以免受糖尿病引起的心脏功能障碍和心肌损伤，而骨膜素过度表达则产生相反的效果。高血糖以 TGF-β/Smad 依赖性方式刺激骨膜素的表达。RNA测序结果显示，骨膜素上调核小体组装蛋白1样2（NAP1L2）的表达，该蛋白招募SIRT3使支链氨基酸（BCAA）分解代谢相关酶BCAT2和PP2Cm启动子上的H3K27ac去乙酰化，从而产生BCAA分解代谢障碍。此外，CF 衍生的骨膜素诱导原代心肌细胞肥大、氧化损伤和炎症。最后，我们发现葡萄糖丁香酸 (GA) 特异性靶向并抑制骨膜素以改善 DCM。总体而言，控制骨膜蛋白表达可能是治疗 DCM 的一种有前景的策略。