Abstract：
As individuals age, there is a gradual decline in cardiopulmonary function, often accompanied by cardiac pump dysfunction leading to increased pulmonary vascular resistance (PVR). Our study aims to investigate the changes in cardiac and pulmonary vascular function associated with aging. Additionally, we aim to explore the impact of phosphodiesterase 9A (PDE9A) inhibition, which has shown promise in treating cardiometabolic diseases, on addressing left ventricle (LV) dysfunction and elevated PVR in aging individuals. Young (3 months old) and aged (32 months old) male C57BL/6 mice were used. Aged mice were treated with the selective PDE9A inhibitor PF04447943 (1 mg/kg/day) through intraperitoneal injections for 10 days. LV function was evaluated using cardiac ultrasound, and PVR was assessed in isolated, ventilated lungs perfused under a constant flow condition. Additionally, changes in PVR were measured in response to perfusion of the endothelium-dependent agonist bradykinin or to nitric oxide (NO) donor sodium nitroprusside (SNP). PDE9A protein expression was measured by Western blots. Our results demonstrate the development of LV diastolic dysfunction and increased PVR in aged mice. The aged mice exhibited diminished decreases in PVR in response to both bradykinin and SNP compared to the young mice. Moreover, the lungs of aged mice showed an increase in PDE9A protein expression. Treatment of aged mice with PF04447943 had no significant effect on LV systolic or diastolic function. However, PF04447943 treatment normalized PVR and SNP-induced responses, though it did not affect the bradykinin response. These data demonstrate a development of LV diastolic dysfunction and increase in PVR in aged mice. We propose that inhibitors of PDE9A could represent a novel therapeutic approach to specifically prevent aging-related pulmonary dysfunction.
摘要：
随着年龄的增长,心肺功能逐渐下降，常伴有心脏泵功能障碍，导致肺血管阻力（PVR）增加。我们的研究旨在探讨与衰老相关的心脏和肺血管功能的变化。此外,我们的目的是探讨磷酸二酯酶9A（PDE9A）抑制的影响，在治疗心脏代谢疾病方面显示出了希望，关于解决老年个体左心室（LV）功能障碍和PVR升高的问题。使用年轻(3月龄)和老年(32月龄)雄性C57BL/6小鼠。通过腹膜内注射用选择性PDE9A抑制剂PF04447943(lmg/kg/天)治疗老年小鼠10天。使用心脏超声评估左心室功能，PVR是孤立地评估的，在恒定流量条件下灌注通气肺。此外,测量了对内皮依赖性激动剂缓激肽或一氧化氮(NO)供体硝普钠(SNP)灌注反应的PVR变化.通过Western印迹测量PDE9A蛋白表达。我们的结果表明，老年小鼠左心室舒张功能障碍和PVR增加。与年轻小鼠相比，老年小鼠对缓激肽和SNP的反应均表现出PVR降低。此外，老年小鼠的肺显示PDE9A蛋白表达增加。用PF04447943处理老年小鼠对LV收缩或舒张功能没有显著影响。然而,PF04447943治疗恢复正常的PVR和SNP诱导的反应，虽然它不影响缓激肽反应。这些数据表明老年小鼠中LV舒张功能障碍的发展和PVR的增加。我们建议PDE9A的抑制剂可以代表一种新颖的治疗方法，以特异性地预防与衰老相关的肺功能障碍。
