Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas 37130-001, Minas Gerais, Brazil; Department of Structural Biology, Federal University of Alfenas, Alfenas 37130-001, Minas Gerais, Brazil.
Fundação Oswaldo Cruz - FIOCRUZ, 21040900 Rio de Janeiro, Brazil.
Life Sci. 2020 Sep 15;257:118067. doi: 10.1016/j.lfs.2020.118067. Epub 2020 Jul 9.
Although renin-angiotensin system (RAS) imbalance is manifested in cardiomyopathies with different etiologies, the impact of RAS effectors on Chagas cardiomyopathy and skeletal myositis is poorly understood. Given that diminazene aceturate (DMZ) shares trypanocidal, angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) stimulatory effects, we investigated the impact of DMZ on cardiomyocytes infection in vitro, renin-angiotensin system, Chagas cardiomyopathy and skeletal myositis in vivo. Cardiomyocytes and T. cruzi were used to evaluate DMZ toxicity in vitro. The impact of 20-days DMZ treatment (1 mg/kg) was also investigated in uninfected and T. cruzi-infected mice as follows: control uninfected and untreated, uninfected treated with DMZ, infected untreated and infected treated with DMZ. DMZ had low toxicity on cardiomyocytes, induced dose-dependent antiparasitic activity on T. cruzi trypomastigotes, and reduced parasite load but not infection rates in cardiomyocytes. DMZ increased ACE2 activity and angiotensin-(1-7) plasma levels but exerted no interference on angiotensin-converting enzyme (ACE) activity, ACE, ACE2 and angiotensin II levels in uninfected and infected mice. DMZ treatment also reduced IFN-γ and IL-2 circulating levels but was ineffective in attenuating parasitemia, MCP-1, IL-10, anti-T. cruzi IgG, nitrite/nitrate and malondialdehyde production, myocarditis and skeletal myositis compared to infected untreated animals. As the antiparasitic effect of DMZ in vitro did not manifest in vivo, this drug exhibited limited relevance to the treatment of Chagas disease. Although DMZ is effective in upregulating angiotensin-(1-7) levels, this molecule does not act as a potent modulator of T. cruzi infection, which can establish heart and skeletal muscle parasitism, lipid oxidation and inflammatory damage, even in the presence of high concentrations of this RAS effector.
尽管肾素-血管紧张素系统（RAS）失衡表现在具有不同病因的心肌病中，但 RAS 效应物对恰加斯心肌病和骨骼肌肌炎的影响知之甚少。鉴于苯硝唑（DMZ）具有杀锥虫、血管紧张素转换酶 2（ACE2）和血管紧张素-(1-7)刺激作用，我们研究了 DMZ 对体外心肌细胞感染、体内 RAS、恰加斯心肌病和骨骼肌肌炎的影响。我们使用心肌细胞和 T. cruzi 来评估 DMZ 的体外毒性。还研究了 20 天 DMZ 治疗（1mg/kg）对未感染和 T. cruzi 感染小鼠的影响，如下所示：未感染且未治疗的对照、未感染且用 DMZ 治疗的、未感染且未用 DMZ 治疗的、感染且未用 DMZ 治疗的、感染且用 DMZ 治疗的。DMZ 对心肌细胞的毒性较低，对 T. cruzi 锥虫的诱导剂量依赖性抗寄生虫活性，并降低寄生虫负荷，但不降低心肌细胞的感染率。DMZ 增加 ACE2 活性和血管紧张素-(1-7)的血浆水平，但对未感染和感染小鼠的 ACE 活性、ACE、ACE2 和血管紧张素 II 水平没有干扰。DMZ 治疗还降低了 IFN-γ 和 IL-2 的循环水平，但对降低寄生虫血症、MCP-1、IL-10、抗 T. cruzi IgG、亚硝酸盐/硝酸盐和丙二醛的产生、心肌炎和骨骼肌肌炎均无效与感染且未经治疗的动物相比。由于 DMZ 在体外的抗寄生虫作用并未在体内表现出来，因此该药物对恰加斯病的治疗相关性有限。尽管 DMZ 能有效上调血管紧张素-(1-7)水平，但这种分子并不能作为 T. cruzi 感染的有效调节剂，即使存在高浓度的这种 RAS 效应物，它也不能对心脏和骨骼肌寄生虫病、脂质氧化和炎症损伤产生影响。
