PDE9A Inhibition Improves Coronary Microvascular Rarefaction and Left Ventricular Diastolic Dysfunction in the ZSF1 Rat Model of HFpEF

IF 1.9 4区医学 Q3 HEMATOLOGY

Microcirculation Pub Date : 2024-09-26 DOI:10.1111/micc.12888

Katie Anne Fopiano, Saltanat Zhazykbayeva, Ibrahim El-Battrawy, Vadym Buncha, William M. Pearson, Davis J. Hardell, Liwei Lang, Nazha Hamdani, Zsolt Bagi

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引用次数: 0

Abstract

Objective

Heart failure with preserved ejection fraction (HFpEF) commonly arises from comorbid diseases, such as hypertension, obesity, and diabetes mellitus. Selective inhibition of phosphodiesterase 9A (PDE9A) has emerged as a potential therapeutic approach for treating cardiometabolic diseases. Coronary microvascular disease (CMD) is one of the key mechanisms contributing to the development of left ventricular (LV) diastolic dysfunction in HFpEF. Our study aimed to investigate the mechanisms by which PDE9A inhibition could ameliorate CMD and improve LV diastolic function in HFpEF.

Methods and Results

The obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat model of HFpEF was employed in which it was found that a progressively developing coronary microvascular rarefaction is associated with LV diastolic dysfunction when compared to lean, nondiabetic hypertensive controls. Obese ZSF1 rats had an increased cardiac expression of PDE9A. Treatment of obese ZSF1 rats with the selective PDE9A inhibitor, PF04447943 (3 mg/kg/day, oral gavage for 2 weeks), improved coronary microvascular rarefaction and LV diastolic dysfunction, which was accompanied by reduced levels of oxidative and nitrosative stress markers, hydrogen peroxide, and 3-nitrotyrosine. Liquid chromatography–mass spectrometry (LC–MS) proteomic analysis identified peroxiredoxins (PRDX) as downregulated antioxidants in the heart of obese ZSF1 rats, whereas Western immunoblots showed that the protein level of PRDX5 was significantly increased by the PF04447943 treatment.

Conclusions

Thus, in the ZSF1 rat model of human HFpEF, PDE9A inhibition improves coronary vascular rarefaction and LV diastolic dysfunction, demonstrating the usefulness of PDE9A inhibitors in ameliorating CMD and LV diastolic dysfunction through augmenting PRDX-dependent antioxidant mechanisms.

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抑制 PDE9A 可改善 ZSF1 高频心衰大鼠模型的冠状动脉微血管稀疏度和左心室舒张功能障碍

目的：射血分数保留型心力衰竭（HFpEF）通常由高血压、肥胖和糖尿病等并发症引起。选择性抑制磷酸二酯酶 9A（PDE9A）已成为治疗心脏代谢疾病的一种潜在疗法。冠状动脉微血管病变（CMD）是导致高频心衰患者左心室舒张功能障碍的关键机制之一。我们的研究旨在探讨抑制 PDE9A 可改善 CMD 和 HFpEF 左心室舒张功能的机制：我们采用肥胖的糖尿病扎克脂肪/自发性高血压心衰 F1 杂交（ZSF1）大鼠作为 HFpEF 模型，发现与瘦弱的非糖尿病高血压对照组相比，逐渐发展的冠状动脉微血管稀疏与左心室舒张功能障碍有关。肥胖 ZSF1 大鼠心脏的 PDE9A 表达增加。用选择性 PDE9A 抑制剂 PF04447943（3 毫克/千克/天，口服，2 周）治疗肥胖 ZSF1 大鼠可改善冠状动脉微血管稀疏和左心室舒张功能障碍，同时降低氧化和亚硝基应激标记物、过氧化氢和 3-硝基酪氨酸的水平。液相色谱-质谱（LC-MS）蛋白质组分析发现，过氧化还原酶（PRDX）是肥胖 ZSF1 大鼠心脏中下调的抗氧化剂，而 Western 免疫印迹显示，PRDX5 蛋白水平在 PF04447943 治疗后显著增加：因此，在人类高密度脂蛋白血症ZSF1大鼠模型中，PDE9A抑制剂可改善冠状动脉血管稀疏和左心室舒张功能障碍，这表明PDE9A抑制剂可通过增强PRDX依赖性抗氧化机制来改善CMD和左心室舒张功能障碍。

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来源期刊

Microcirculation 医学-外周血管病

CiteScore

5.00

自引率

4.20%

发文量

审稿时长

6-12 weeks

期刊介绍： The journal features original contributions that are the result of investigations contributing significant new information relating to the vascular and lymphatic microcirculation addressed at the intact animal, organ, cellular, or molecular level. Papers describe applications of the methods of physiology, biophysics, bioengineering, genetics, cell biology, biochemistry, and molecular biology to problems in microcirculation. Microcirculation also publishes state-of-the-art reviews that address frontier areas or new advances in technology in the fields of microcirculatory disease and function. Specific areas of interest include: Angiogenesis, growth and remodeling; Transport and exchange of gasses and solutes; Rheology and biorheology; Endothelial cell biology and metabolism; Interactions between endothelium, smooth muscle, parenchymal cells, leukocytes and platelets; Regulation of vasomotor tone; and Microvascular structures, imaging and morphometry. Papers also describe innovations in experimental techniques and instrumentation for studying all aspects of microcirculatory structure and function.