Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon.
Faculté de Médecine, Laboratoire de Recherche en Physiologie et Physiopathologie, LRPP, Pôle Technologie Santé, Université Saint Joseph, Beirut, Lebanon.
Life Sci. 2021 Oct 15;283:119857. doi: 10.1016/j.lfs.2021.119857. Epub 2021 Jul 30.
Diabetic cardiomyopathy (DCM) accomodates a spectrum of cardiac abnormalities. This study aims to investigate whether DCM is associated with changes in cyclic adenosine 3'-5' monophosphate (cAMP) signaling, particularly cyclic nucleotide phosphodiesterases (PDEs).
Type 1 diabetes (T1D) was induced in rats by streptozotocin (STZ, 65 mg/kg) injection. Myocardial remodeling, structure and function were evaluated by histology and echocardiography, respectively. We delineated the sequential changes affecting cAMP signaling and characterized the expression pattern of the predominant cardiac PDE isoforms (PDE 1-5) and β-adrenergic (β-AR) receptors at 4, 8 and 12 weeks following diabetes induction, by real-time quantitative PCR and Western blot. cAMP levels were measured by immunoassays.
T1D-induced DCM was associated with cardiac remodeling, steatosis and fibrosis. Upregulation of β-AR receptor transcripts was noted in diabetic hearts at 4 weeks along with an increase in cAMP levels and an upregulation in the ejection fraction and fraction shortening. However, β-AR receptors expression remained unchanged regardless of the disease stage. Moreover, we noted an early and specific upregulation of cardiac PDE1A, PDE2A, PDE4B, PDE4D and PDE5A expression at week 4, followed by increases in PDE3A levels in diabetic hearts at week 8. However, DCM was not associated with changes in PDE4A gene expression irrespective of the disease stage.
We show for the first time differential and time-specific regulations in cardiac PDEs, data that may prove useful in proposing new therapeutic approaches in T1D-induced DCM.
糖尿病心肌病（DCM）可引起一系列心脏异常。本研究旨在探讨 DCM 是否与环磷酸腺苷 3'-5' 单磷酸（cAMP）信号转导的变化有关，特别是环核苷酸磷酸二酯酶（PDEs）。
链脲佐菌素（STZ，65mg/kg）注射诱导大鼠 1 型糖尿病（T1D）。通过组织学和超声心动图分别评估心肌重构、结构和功能。我们描绘了影响 cAMP 信号转导的顺序变化，并通过实时定量 PCR 和 Western blot 分别在糖尿病诱导后 4、8 和 12 周时，描述了主要心脏 PDE 同工酶（PDE1-5）和β-肾上腺素能（β-AR）受体的表达模式。通过免疫测定法测量 cAMP 水平。
T1D 诱导的 DCM 与心脏重构、脂肪变性和纤维化有关。在糖尿病心脏中，β-AR 受体转录本在 4 周时上调，同时 cAMP 水平升高，射血分数和缩短分数增加。然而，β-AR 受体表达在疾病的任何阶段都没有变化。此外，我们还发现心脏 PDE1A、PDE2A、PDE4B、PDE4D 和 PDE5A 的表达在第 4 周时出现早期且特异性上调，随后在第 8 周时糖尿病心脏中 PDE3A 水平增加。然而，DCM 与 PDE4A 基因表达的变化无关，与疾病阶段无关。
我们首次显示了心脏 PDE 的差异和时间特异性调节，这些数据可能有助于提出治疗 T1D 诱导的 DCM 的新治疗方法。
