Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
Institute of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
Int J Mol Sci. 2018 Sep 22;19(10):2882. doi: 10.3390/ijms19102882.
Atherosclerosis is strongly associated with cardiac dysfunction and heart failure. Besides microvascular dysfunction and diminishment of the cardiac nitric oxide-Protein Kinase G (NO-PKG) pathway, recent evidence suggests that phosphodiesterase 9A (PDE9A) enzyme has an unfavorable role in pathological changes. Here, we characterized a rabbit model that shows cardiac dysfunction as a result of an atherogenic diet, and examined the myocardial PDE9A signaling. Rabbits were divided into Control (normal diet) and HC (atherogenic diet) groups. Cardiac function was evaluated by echocardiography. Vascular function was assessed, along with serum biomarkers. Histological stains were conducted, expression of selected proteins and cyclic guanosine monophosphate (cGMP) levels were determined. Signs of diastolic dysfunction were shown in HC animals, along with concentric hypertrophy and interstitial fibrosis. Endothelial function was diminished in HC rabbits, along with marked reduction in the aortic lumen, and increased left ventricle outflow tract (LVOT) pressures. A significant increase was shown in myocardial PDE9A levels in HC animals with unchanged vasodilator-stimulated phosphoprotein (VASP) phosphorylation and cGMP levels. Upregulation of PDE9A may be associated with early stage of cardiac dysfunction in atherosclerotic conditions. Since PDE9A is involved in cGMP degradation and in deactivation of the cardioprotective PKG signaling pathway, it may become an encouraging target for future investigations in atherosclerotic diseases.
动脉粥样硬化与心脏功能障碍和心力衰竭密切相关。除了微血管功能障碍和心脏一氧化氮蛋白激酶 G（NO-PKG）途径减少外，最近的证据表明，磷酸二酯酶 9A（PDE9A）酶在病理变化中具有不利作用。在这里，我们描述了一种兔模型，该模型由于动脉粥样硬化饮食而导致心脏功能障碍，并检查了心肌 PDE9A 信号。将兔子分为对照组（正常饮食）和 HC 组（动脉粥样硬化饮食）。通过超声心动图评估心功能。评估血管功能和血清生物标志物。进行组织学染色，测定选定蛋白质的表达和环鸟苷酸（cGMP）水平。HC 动物表现出舒张功能障碍的迹象，伴有同心性肥大和间质纤维化。HC 兔的内皮功能减弱，主动脉腔明显缩小，左心室流出道（LVOT）压力增加。HC 动物的心肌 PDE9A 水平显著升高，而血管扩张刺激磷酸蛋白（VASP）磷酸化和 cGMP 水平不变。PDE9A 的上调可能与动脉粥样硬化条件下心脏功能障碍的早期阶段有关。由于 PDE9A 参与 cGMP 降解和心脏保护性 PKG 信号通路的失活，因此它可能成为动脉粥样硬化疾病未来研究的一个有希望的靶点。
