Simvastatin Improves Cardiac Function through Notch 1 Activation in BALB/c Mice with Chronic Chagas Cardiomyopathy

被引:16
作者
Guzman-Rivera, Daniela [1 ]
Liempi, Ana [2 ]
Gonzalez-Herrera, Fabiola [1 ]
Fuentes-Retamal, Sebastian [1 ]
Carrillo, Ileana [1 ]
Abarca, Patricio [1 ]
Castillo, Christian [2 ]
Kemmerling, Ulrike [2 ]
Pesce, Barbara [1 ]
Diego Maya, Juan [1 ]
机构
[1] Univ Chile, Fac Med, Inst Biomed Sci, Clin & Mol Pharmacol Program, Santiago, Chile
[2] Univ Chile, Inst Biomed Sci, Anat & Dev Biol Program, Santiago, Chile
关键词
Chagas cardiomyopathy; Notch; 1; simvastatin; TRIGGERED LIPOXIN A(4); ASPIRIN; INFLAMMATION; EXPRESSION; RESOLUTION;
D O I
10.1128/AAC.02141-19
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Chagas disease, caused by the protozoan Trypanosome cruzi, endemic in Latin America but distributed worldwide because of migration. Without appropriate treatment, the disease progresses from an acute asymptomatic phase to a chronic, progressive inflammatory cardiomyopathy causing heart failure and death. Despite specific trypanocidal therapy, heart damage progression cannot be stopped or reversed. Statins, as part of their pleiotropic actions, can modulate chagasic myocarditis by inducing the production of 15-epi-lipoxin A(4) (15-epi-LXA(4)), a proresolution lipid mediator in inflammation. Furthermore, several reports suggest that simvastatin activates the Notch pathway after stroke in cerebral endothelial cells, enhancing blood flow by promoting angiogenesis. Thus, statins are an attractive therapeutic strategy for modulating the Notch pathway to reverse the chronic heart damage induced by T. cruzi. BALB/c mice chronically infected with T. cruzi were treated with 1 mg/kg/day simvastatin or 25 mu g/kg/day 15-epi-LXA 4 for 20 days. During the treatment period, cardiac function was evaluated by echocardiography. At 80 days postinfection, the heart tissues were assessed for Notch 1 activity. T. cruzi infection activated the Notch 1 pathway, and simvastatin (but not 15-epi-lipoxin A(4)) produced a further increase in that activity, correlating with improvement in the ejection fraction and histopathologic findings typical of T. cruzi infection, including improvements in inflammation and fibrosis. Moreover, simvastatin increased the number of isolectin B4-positive cells, suggesting active angiogenesis in the chronically infected hearts without alteration of the parasitic load. Simvastatin, probably acting through the Notch 1 pathway, decreases inflammation, improving cardiac function in mice chronically infected with T. cruzi.
引用
收藏
页数:12
相关论文
共 34 条
  • [1] Notch signaling: Cell fate control and signal integration in development
    Artavanis-Tsakonas, S
    Rand, MD
    Lake, RJ
    [J]. SCIENCE, 1999, 284 (5415) : 770 - 776
  • [2] Simvastatin and Benznidazole-Mediated Prevention of Trypanosoma cruzi-Induced Endothelial Activation: Role of 15-epi-lipoxin A4 in the Action of Simvastatin
    Campos-Estrada, Carolina
    Liempi, Ana
    Gonzalez-Herrera, Fabiola
    Lapier, Michel
    Kemmerling, Ulrike
    Pesce, Barbara
    Ferreira, Jorge
    Lopez-Munoz, Rodrigo
    Maya, Juan D.
    [J]. PLOS NEGLECTED TROPICAL DISEASES, 2015, 9 (05):
  • [3] ATL-1, an analogue of aspirin-triggered lipoxin A4, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor
    Cezar-de-Mello, P. F. T.
    Vieira, A. M.
    Nascimento-Silva, V.
    Villela, C. G.
    Barja-Fidalgo, C.
    Fierro, I. M.
    [J]. BRITISH JOURNAL OF PHARMACOLOGY, 2008, 153 (05) : 956 - 965
  • [4] Atorvastatin promotes presenilin-1 expression and Notch1 activity and increases neural progenitor cell proliferation after stroke
    Chen, Jieli
    Zacharek, Alex
    Li, Ang
    Cui, Xu
    Roberts, Cynthia
    Lu, Mei
    Chopp, Michael
    [J]. STROKE, 2008, 39 (01) : 220 - 226
  • [5] Analytical Performance of a Multiplex Real-Time PCR Assay Using TaqMan Probes for Quantification of Trypanosoma cruzi Satellite DNA in Blood Samples
    Duffy, Tomas
    Cura, Carolina I.
    Ramirez, Juan C.
    Abate, Teresa
    Cayo, Nelly M.
    Parrado, Rudy
    Diaz Bello, Zoraida
    Velazquez, Elsa
    Munoz-Calderon, Arturo
    Juiz, Natalia A.
    Basile, Joaquin
    Garcia, Lineth
    Riarte, Adelina
    Nasser, Julio R.
    Ocampo, Susana B.
    Yadon, Zaida E.
    Torrico, Faustino
    Alarcon de Noya, Belkisyole
    Ribeiro, Isabela
    Schijman, Alejandro G.
    [J]. PLOS NEGLECTED TROPICAL DISEASES, 2013, 7 (01):
  • [6] The Notch pathway: a novel target for myocardial remodelling therapy?
    Ferrari, Roberto
    Rizzo, Paola
    [J]. EUROPEAN HEART JOURNAL, 2014, 35 (32) : 2140 - U86
  • [7] Francisco AF, 2018, ANTIMICROB AGENTS CH, V62, DOI [10.1128/AAC.00832-18, 10.1128/aac.00832-18]
  • [8] Simvastatin Attenuates Endothelial Activation through 15-Epi-Lipoxin A4 Production in Murine Chronic Chagas Cardiomyopathy (vol 61, e02137-16, 2017)
    Gonzalez-Herrera, Fabiola
    Cramer, Allysson
    Pimentel, Pollyana
    Castillo, Christian
    Liempi, Ana
    Kemmerling, Ulrike
    Machado, Fabiana S.
    Maya, Juan D.
    [J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2017, 61 (05)
  • [9] The updated biology of hypoxia-inducible factor
    Greer, Samantha N.
    Metcalf, Julie L.
    Wang, Yi
    Ohh, Michael
    [J]. EMBO JOURNAL, 2012, 31 (11) : 2448 - 2460
  • [10] Integrated Regulation of Toll-like Receptor Responses by Notch and Interferon-γ Pathways
    Hu, Xiaoyu
    Chung, Allen Y.
    Wu, Indira
    Foldi, Julia
    Chen, Janice
    Ji, Jong Dae
    Tateya, Tomoko
    Kang, Young Jun
    Han, Jiahuai
    Gessler, Manfred
    Kageyama, Ryoichiro
    Ivashkiv, Lionel B.
    [J]. IMMUNITY, 2008, 29 (05) : 691 - 703