Programa de Pós-Graduação em Biociências Aplicadas à Saúde, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil; Instituto Federal do Sul de Minas Gerais, Pouso Alegre, 37560-250, Minas Gerais, Brazil.
Programa de Pós-Graduação em Ciências Biológicas, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil.
Acta Trop. 2023 Aug;244:106950. doi: 10.1016/j.actatropica.2023.106950. Epub 2023 May 19.
The relationship between redox imbalance and cardiovascular senescence in infectious myocarditis is unknown. Thus, the aim of this study was to investigate whether cardiomyocytes parasitism, oxidative stress and contractile dysfunction can be correlated to senescence-associated β-galactosidase (SA-β-Gal) activity in Trypanosoma cruzi-infection in vitro and in vivo.
Uninfected, T. cruzi-infected untreated and benznidazole (BZN)-treated H9c2 cardiomyocytes and rats were investigated. Parasitological, prooxidant, antioxidant, microstructural, and senescence-associated markers were quantified in vitro and in vivo.
T. cruzi infection triggered intense cardiomyocytes parasitism in vitro and in vivo, which was accompanied by reactive oxygen species (ROS) upregulation, lipids, proteins and DNA oxidation in cardiomyocytes and cardiac tissue. Oxidative stress was parallel to microstructural cell damage (e.g., increased cardiac toponin I levels) and contractile dysfunction in cardiomyocytes in vitro and in vivo, whose severity accompanied a premature cellular senescence-like phenotype revealed by increased senescence-associated β-galactosidase (SA-β-Gal) activity and DNA oxidation (8-OHdG). Cellular parasitism (e.g., infection rate and parasite load), myocarditis and T. cruzi-induced prooxidant responses were attenuated by early BZN administration to interrupt the progression of T. cruzi infection, protecting against SA-β-gal-based premature cellular senescence, microstructural damage and contractile deterioration in cardiomyocytes from T. cruzi-infected animals.
Our findings indicated that cell parasitism, redox imbalance and contractile dysfunction were correlated to SA-β-Gal-based cardiomyocytes premature senescence in acute T. cruzi infection. Therefore, in addition to controlling parasitism, inflammation and oxidative stress; inhibiting cardiomyocytes premature senescence should be further investigated as an additional target of specific Chagas disease therapeutics.
氧化还原失衡与感染性心肌炎中心血管衰老的关系尚不清楚。因此，本研究旨在探讨体外和体内感染克氏锥虫时，心肌细胞寄生、氧化应激和收缩功能障碍是否与衰老相关的β-半乳糖苷酶（SA-β-Gal）活性相关。
研究了未感染、未经处理的克氏锥虫感染和苯并硝唑（BZN）处理的 H9c2 心肌细胞以及大鼠。在体外和体内定量检测寄生虫学、促氧化剂、抗氧化剂、微观结构和衰老相关标志物。
克氏锥虫感染在体外和体内引发强烈的心肌细胞寄生，同时伴有活性氧（ROS）上调、心肌细胞和心脏组织中的脂质、蛋白质和 DNA 氧化。氧化应激与心肌细胞的微观结构细胞损伤（例如，心脏肌钙蛋白 I 水平升高）和收缩功能障碍平行，其严重程度伴随着由衰老相关β-半乳糖苷酶（SA-β-Gal）活性和 DNA 氧化（8-OHdG）增加所揭示的早期细胞衰老样表型。早期 BZN 给药可减轻细胞寄生（例如，感染率和寄生虫负荷）、心肌炎和克氏锥虫诱导的促氧化剂反应，从而阻止克氏锥虫感染的进展，防止来自感染克氏锥虫动物的心肌细胞中基于 SA-β-Gal 的过早细胞衰老、微观结构损伤和收缩恶化。
我们的发现表明，细胞寄生、氧化还原失衡和收缩功能障碍与急性克氏锥虫感染中的 SA-β-Gal 基于心肌细胞的过早衰老相关。因此，除了控制寄生虫、炎症和氧化应激外；抑制心肌细胞的过早衰老应该作为特异性恰加斯病治疗的另一个靶点进一步研究。
