Division of Molecular Medicine, Department of Anesthesiology, Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Division of Molecular Medicine, Department of Anesthesiology, Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Redox Biol. 2022 Dec;58:102521. doi: 10.1016/j.redox.2022.102521. Epub 2022 Nov 16.
Aortic aneurysms are prevalent and severe vascular diseases with high mortality from unpredicted ruptures, while the only treatment option is surgical correction of large aneurysms with considerable risk. We have shown that folic acid (FA) is highly effective in alleviating development of aneurysms although not sufficient to completely attenuate aneurysm formation. Here, we examined therapeutic effects on aneurysms of combining FA with Nifedipine as novel and potentially more effective oral medication. Oral administration with FA (15 mg/kg/day) significantly reduced incidence of AAA from 85.71% to 18.75% in Ang II-infused apolipoprotein E (apoE) null mice, while combination of FA with Nifedipine (1.5, 5.0 or 20 mg/kg/day) substantially and completely further reduced incidence of AAA to 12.5%, 11.76% and 0.00% respectively in a dose-dependent manner. The combinatory therapy substantially and completely further alleviated enlargement of abdominal aortas defined by ultrasound, vascular remodeling characterized by elastin degradation and adventitial hypertrophy, as well as aortic superoxide production and eNOS uncoupling activity also in a dose-dependent manner, with combination of FA with 20 mg/kg/day Nifedipine attenuating all of these features by 100% to control levels. Aortic NO and HB bioavailabilities were also dose-dependently further improved by combining FA with Nifedipine. These data establish entirely innovative and robust therapeutic regime of FA combined with Nifedipine for the treatment of aortic aneurysms. The comminatory therapy can serve as a first-in-class and most effective oral medication for aortic aneurysms, which can be rapidly translated into clinical practice to revolutionize management of the devastating vascular diseases of aortic aneurysms known as silent killers.
主动脉瘤是一种常见且严重的血管疾病，其死亡率很高，原因是突发破裂，而唯一的治疗选择是对大型动脉瘤进行手术矫正，但风险较大。我们已经证明，叶酸（FA）在缓解动脉瘤发展方面非常有效，尽管不足以完全抑制动脉瘤形成。在这里，我们研究了将 FA 与硝苯地平联合用于治疗动脉瘤的疗效，这是一种新颖的、潜在更有效的口服药物。在血管紧张素 II 输注的载脂蛋白 E（apoE）基因敲除小鼠中，每天口服 FA（15mg/kg）可使 AAA 的发生率从 85.71%降低至 18.75%，而 FA 与硝苯地平（1.5、5.0 或 20mg/kg）联合使用则可显著且完全地将 AAA 的发生率进一步降低至分别为 12.5%、11.76%和 0.00%，呈剂量依赖性。联合治疗还可显著且完全地进一步缓解超声定义的腹主动脉扩张、由弹性蛋白降解和外膜肥大引起的血管重塑，以及主动脉超氧化物产生和 eNOS 解偶联活性，FA 与 20mg/kg 硝苯地平联合使用可将这些特征全部降低至对照水平，降低幅度为 100%。FA 与硝苯地平联合使用还可剂量依赖性地进一步提高主动脉 NO 和 HB 的生物利用度。这些数据建立了 FA 联合硝苯地平治疗主动脉瘤的全新、有效的治疗方案。联合治疗可作为治疗主动脉瘤的首创新药和最有效口服药物，可迅速转化为临床实践，彻底改变被称为“沉默杀手”的主动脉瘤这一破坏性血管疾病的治疗方法。
