Background

Cardiac fibrosis is an important cause of heart failure (HF) after myocardial infarction (MI). Cyclin-dependent kinase inhibitor 2b (CDKN2b) regulates the cell cycle by encoding the p15 protein and participates in the development of various tumours. However, the role of CDKN2b/p15 in cardiac fibrosis and HF after MI remains unclear.

Methods

Lentivirus was used to induce the silence and overexpression of CDKN2b. Cardiac function was detected with the use of echocardiography. Immunohistochemistry, immunofluorescence, Western blotting, Cell Counting Kit 8, and wound healing assay were used to illustrate the potential mechanism associated with CDKN2b.

Results

The p15 protein expression was significantly down-regulated in both human and mouse failing hearts. Cardiac down-regulation of CDKN2b promoted myocardial fibrosis and worsened cardiac function in MI mice, while systemic CDKN2b silencing induced diastolic dysfunction in vivo. In addition, cardiac overexpression of CDKN2b ameliorated cardiac fibrosis and improved cardiac function in MI mice. Mechanistically, silencing CDKN2b gene enhanced the phosphorylation of retinoblastoma (Rb) protein and reinforced the migration and proliferation capabilities of cardiac fibroblasts. B Lymphoma Mo-MLV insertion region 1 homolog (BMI1) was up-regulated in failing heart and inversely regulated the expression of CDKN2b/p15 and the phosphorylation of Rb protein. The BMI1-p15-Rb signalling pathway is a potential mechanism of ischemia-induced cardiac fibrosis and HF.

Conclusions

Cardiac fibrosis and heart function could be worsened by the down-regulation and relieved by the up-regulation of CDKN2b/p15 in ischemia-induced HF via regulating the proliferation and migration capabilities of cardiac fibroblasts. These effects could be partially explained by the regulation of the BMI1-p15-Rb signalling pathway.

中文翻译：

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细胞周期蛋白依赖性激酶抑制剂 2b 通过 BMI1-p15-Rb 信号通路控制缺血性心力衰竭的纤维化和功能变化

背景

心脏纤维化是心肌梗塞 (MI) 后心力衰竭 (HF) 的重要原因。细胞周期蛋白依赖性激酶抑制剂 2b (CDKN2b) 通过编码 p15 蛋白调节细胞周期并参与各种肿瘤的发展。然而，CDKN2b/p15 在 MI 后心脏纤维化和 HF 中的作用仍不清楚。

方法

慢病毒用于诱导 CDKN2b 的沉默和过表达。使用超声心动图检测心脏功能。免疫组织化学、免疫荧光、蛋白质印迹、细胞计数试剂盒 8 和伤口愈合试验用于说明与 CDKN2b 相关的潜在机制。

结果

p15 蛋白表达在人和小鼠衰竭心脏中均显着下调。CDKN2b 的心脏下调促进了 MI 小鼠的心肌纤维化和心脏功能恶化，而全身性 CDKN2b 沉默诱导了体内舒张功能障碍. 此外，CDKN2b 的心脏过表达可改善 MI 小鼠的心脏纤维化并改善心脏功能。从机制上讲，沉默 CDKN2b 基因增强了视网膜母细胞瘤 (Rb) 蛋白的磷酸化，并增强了心脏成纤维细胞的迁移和增殖能力。B 淋巴瘤 Mo-MLV 插入区 1 同源物 (BMI1) 在衰竭心脏中上调，并反向调节 CDKN2b/p15 的表达和 Rb 蛋白的磷酸化。BMI1-p15-Rb 信号通路是缺血诱导的心脏纤维化和 HF 的潜在机制。

结论

通过调节心脏成纤维细胞的增殖和迁移能力，缺血诱导的 HF 中，CDKN2b/p15 的下调可能会加重心脏纤维化和心脏功能，而 CDKN2b/p15 的上调可能会缓解心脏纤维化和心脏功能。这些影响可以部分通过 BMI1-p15-Rb 信号通路的调节来解释。