Phosphodiesterase 9a Inhibition in Mouse Models of Diastolic Dysfunction

<strong>Background:</strong> Low myocardial cGMP-PKG activity has been associated with increased cardiomyocyte diastolic stiffness in HFpEF. cGMP is mainly hydrolyzed by phosphodiesterases (PDE) 5a and 9a. Importantly, PDE9a expression has been reported to be upregulated in human HFpEF myocardium and chronic administration of a PDE9a inhibitor reverses pre-established cardiac hypertrophy and systolic dysfunction in mice subjected to TAC (Transverse Aortic Constriction). We hypothesized that inhibiting PDE9a activity ameliorates diastolic dysfunction. <strong>Methods and Results:</strong> Two diastolic dysfunction mouse models were studied: 1) TAC-DOCA (deoxycorticosterone acetate) and 2) <em>Leprdb/db</em>, a metabolically induced diastolic dysfunction model. The effect of acute PDE9a inhibition was investigated in intact cardiomyocytes isolated from TAC-DOCA mice; no acute cellular stiffness reduction was found. For chronic inhibition, mice were implanted with osmotic minipumps containing either PDE9a inhibitor or vehicle. PDE9a inhibition (5 and 8 mg/kg/day) resulted in reduced LV chamber stiffness in TAC-DOCA, but not in <em>Leprdb/db</em> mice. Passive cardiomyocyte stiffness was reduced by chronic PDE9a inhibition, with no differences in myocardial fibrosis or cardiac morphometry. PDE9a inhibition increased the ventricular-arterial (VA) coupling ratio, reflecting impaired systolic function. <strong>Conclusions:</strong> Chronic PDE9a inhibition lowers LV chamber stiffness in TAC-DOCA mice. However, the usefulness of PDE9a inhibition to treat high diastolic stiffness may be limited as the required PDE9a inhibitor dose also impairs systolic function, observed as a decline in ventricular-arterial coordination, in this model. <br> <em>For inquiries regarding the contents of this dataset, please contact the Corresponding Author listed in the README.txt file. Administrative inquiries (e.g., removal requests, trouble downloading, etc.) can be directed to [e-mail]</em>

**背景：** 心肌组织中环磷酸鸟苷-蛋白激酶G（cGMP-PKG）活性低下与射血分数保留型心力衰竭（HFpEF）中心肌细胞舒张僵硬度升高相关。环磷酸鸟苷（cGMP）主要由磷酸二酯酶（PDE）5a和9a水解代谢。值得注意的是，已有研究报道人类HFpEF心肌组织中PDE9a的表达上调，且长期给予PDE9a抑制剂可逆转经主动脉横向缩窄（Transverse Aortic Constriction，TAC）造模小鼠中已建立的心肌肥厚与收缩功能障碍。本研究推测抑制PDE9a活性可改善舒张功能障碍。
**方法与结果：** 本研究采用两种舒张功能障碍小鼠模型：1）TAC联合醋酸脱氧皮质酮（deoxycorticosterone acetate，DOCA）模型；2）*Leprdb/db*小鼠，一种代谢诱导型舒张功能障碍模型。本研究检测了急性PDE9a抑制对TAC-DOCA小鼠分离的完整心肌细胞的影响，未观察到细胞僵硬度的急性降低。对于长期抑制实验，小鼠被植入渗透微泵，分别灌注PDE9a抑制剂或赋形剂。给予PDE9a抑制剂（5和8 mg/kg/天）可降低TAC-DOCA小鼠的左心室（Left Ventricle，LV）腔僵硬度，但对*Leprdb/db*小鼠无此效果。长期PDE9a抑制可降低心肌细胞被动僵硬度，且心肌纤维化或心脏形态计量学指标无显著差异。PDE9a抑制可升高心室-动脉（ventricular-arterial，VA）耦联比值，这一现象反映了收缩功能的受损。
**结论：** 长期PDE9a抑制可降低TAC-DOCA小鼠的左心室腔僵硬度。然而，在该模型中，所需的PDE9a抑制剂剂量同时会损害收缩功能，表现为心室-动脉协调能力下降，因此PDE9a抑制用于治疗舒张僵硬度升高的应用潜力可能受限。

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