Patients with type 2 diabetes have a substantial risk of developing cardiovascular disease. Phosphodiesterase 4 (PDE4) dysregulation is of pathophysiological importance in metabolic disorders. To determine the role of PDE4 in diabetic cardiac dysfunction, mice fed with high-fat diet (HFD) were treated by pharmacological inhibition of PDE4 or cardiac specific knocking down of PDE4D. Mice on HFD developed diabetes and cardiac dysfunction with increased cardiac PDE4D5 expression. PDE4 inhibitor roflumilast can reverse hyperglycemia and cardiac dysfunction, accompanied by the decrease of PDE4D expression and increase of muscle-specific microRNA miR-1 level in hearts. Either cardiac specific PDE4D knockdown or miR-1 overexpression significantly reversed cardiac dysfunction in HFD-mice, despite persistence of hyperglycemia. Gain- and loss-of-function studies of PDE4D in cardiomyocytes implicated that inhibition of insulin-induced PDE4D protected cardiac hypertrophy by preserving miR-1 expression in cardiomyocytes through promoting cAMP-CREB-Sirt1 signaling-induced SERCA2a expression. We further revealed that insulin also induced PDE4D expression in cardiac fibroblasts, which causes cardiac fibrosis through TGF-β1 signaling-mediated miR-1 reduction. Importantly, the expression of PDE4D5 was increased in human failing hearts with diabetes. These studies elucidate a novel mechanism by which hyperinsulinemia-induced cardiac PDE4D expression contributes to diabetic cardiac remodeling through reducing the expression of miR-1 and upregulation of miR-1 target hypertrophy and fibrosis-associated genes. Our study suggests a therapeutic potential of PDE4 inhibitor roflumilast in preventing or treating cardiac dysfunction in diabetes in addition to lowering glucose.

中文翻译：

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罗氟司特介导的磷酸二酯酶 4D 抑制逆转糖尿病相关的心脏功能障碍和重塑：超越血糖降低的影响

2型糖尿病患者发生心血管疾病的风险很大。磷酸二酯酶 4 (PDE4) 失调在代谢紊乱中具有重要的病理生理学意义。为了确定 PDE4 在糖尿病心功能不全中的作用，喂食高脂肪饮食 (HFD) 的小鼠通过药物抑制 PDE4 或心脏特异性敲除 PDE4D 进行治疗。HFD 小鼠发展为糖尿病和心脏功能障碍，心脏 PDE4D5 表达增加。PDE4抑制剂罗氟司特可逆转高血糖和心功能不全，伴随心脏中PDE4D表达降低和肌肉特异性microRNA miR-1水平升高。尽管高血糖持续存在，但心脏特异性 PDE4D 敲低或 miR-1 过表达均显着逆转了 HFD 小鼠的心功能不全。心肌细胞中 PDE4D 的功能增益和功能丧失研究表明，抑制胰岛素诱导的 PDE4D 通过促进 cAMP-CREB-Sirt1 信号传导诱导的 SERCA2a 表达来保护心肌细胞中 miR-1 的表达，从而保护心脏肥大。我们进一步揭示了胰岛素还诱导心脏成纤维细胞中的 PDE4D 表达，其通过 TGF-β1 信号介导的 miR-1 减少引起心脏纤维化。重要的是，PDE4D5 的表达在患有糖尿病的人类衰竭心脏中增加。这些研究阐明了一种新机制，高胰岛素血症诱导的心脏 PDE4D 表达通过降低 miR-1 的表达和上调 miR-1 靶肥大和纤维化相关基因来促进糖尿病心脏重塑。