Dataset Information

Inhibition of SREBP Improves Cardiac Lipidopathy, Improves Endoplasmic Reticulum Stress, and Modulates Chronic Chagas Cardiomyopathy.

ABSTRACT: Background Trypanosoma cruzi is an intracellular parasite that causes debilitating chronic Chagas cardiomyopathy (CCM), for which there is no effective drug or vaccine. Previously, we demonstrated increased cardiac lipid accumulation and endoplasmic reticulum stress in mice with CCM. Increased endoplasmic reticulum stress may lead to uncontrolled SREBP (sterol regulatory element-binding protein) activation and lipotoxicity in the myocardium during the intermediate stage of infection and result in progression to chronic CCM. Therefore, we investigated whether inhibiting SREBP activation modulates CCM progression in T cruzi-infected mice. Methods and Results T cruzi-infected cultured cardiomyocytes (3:1 multiplicity of infection; 24 hours postinfection) were incubated with betulin (3 ?mol/L per mL), an SREBP inhibitor, for 24 hours. Quantitative polymerase chain reaction and Western blotting analyses demonstrated a significant reduction in SREBP activation, lipid biosynthesis, and endoplasmic reticulum stress in betulin-treated infected cells compared with untreated cells. T cruzi infected (103 trypomastigotes of the Brazil strain) Swiss mice were fed a customized diet containing betulin during the intermediate stage (40 days postinfection) until the chronic stage (120 DPI). Cardiac ultrasound imaging and histological and biochemical analyses demonstrated anatomical and functional improvements in betulin-treated, infected mice compared with untreated controls: we observed a significant reduction in cholesterol/fatty acid synthesis that may result in the observed cardiac reduction in cardiac lipid accumulation, mitochondrial and endoplasmic reticulum stress, and ventricular enlargement. Conclusions Our study (in vitro and vivo) demonstrates that inhibition of cardiac SREBP activation reduces cardiac damage during T cruzi infection and modulates CCM in a murine Chagas model.

SUBMITTER: Ayyappan JP

PROVIDER: S-EPMC7033903 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inhibition of SREBP Improves Cardiac Lipidopathy, Improves Endoplasmic Reticulum Stress, and Modulates Chronic Chagas Cardiomyopathy.

Ayyappan Janeesh Plakkal JP Lizardo Kezia K Wang Sean S Yurkow Edward E Nagajyothi Jyothi F JF

Journal of the American Heart Association 20200124 3

Background <i>Trypanosoma cruzi</i> is an intracellular parasite that causes debilitating chronic Chagas cardiomyopathy (CCM), for which there is no effective drug or vaccine. Previously, we demonstrated increased cardiac lipid accumulation and endoplasmic reticulum stress in mice with CCM. Increased endoplasmic reticulum stress may lead to uncontrolled SREBP (sterol regulatory element-binding protein) activation and lipotoxicity in the myocardium during the intermediate stage of infection and r ...[more]

PMID: 31973605

Similar Datasets

Project description:Endoplasmic reticulum (ER) stress leads to endothelial dysfunction which is commonly associated in the pathogenesis of several cardiovascular diseases. We explored the vascular protective effects of chronic treatment with paeonol (2'-hydroxy-4'-methoxyacetophenone), the major compound from the root bark of Paeonia suffruticosa on ER stress-induced endothelial dysfunction in mice. Male C57BL/6J mice were injected intraperitoneally with ER stress inducer, tunicamycin (1 mg/kg/week) for 2 weeks to induce ER stress. The animals were co-administered with or without paeonol (20 mg/kg/oral gavage), reactive oxygen species (ROS) scavenger, tempol (20 mg/kg/day) or ER stress inhibitor, tauroursodeoxycholic acid (TUDCA, 150 mg/kg/day) respectively. Blood pressure and body weight were monitored weekly and at the end of treatment, the aorta was isolated for isometric force measurement. Protein associated with ER stress (GRP78, ATF6 and p-eIF2α) and oxidative stress (NOX2 and nitrotyrosine) were evaluated using Western blotting. Nitric oxide (NO) bioavailability were determined using total nitrate/nitrite assay and western blotting (phosphorylation of eNOS protein). ROS production was assessed by en face dihydroethidium staining and lucigenin-enhanced chemiluminescence assay, respectively. Our results revealed that mice treated with tunicamycin showed an increased blood pressure, reduction in body weight and impairment of endothelium-dependent relaxations (EDRs) of aorta, which were ameliorated by co-treatment with either paeonol, TUDCA and tempol. Furthermore, paeonol reduced the ROS level in the mouse aorta and improved NO bioavailability in tunicamycin treated mice. These beneficial effects of paeonol observed were comparable to those produced by TUDCA and tempol, suggesting that the actions of paeonol may involve inhibition of ER stress-mediated oxidative stress pathway. Taken together, the present results suggest that chronic treatment with paeonol preserved endothelial function and normalized blood pressure in mice induced by tunicamycin in vivo through the inhibition of ER stress-associated ROS.

Dataset Information

Inhibition of SREBP Improves Cardiac Lipidopathy, Improves Endoplasmic Reticulum Stress, and Modulates Chronic Chagas Cardiomyopathy.

Publications

Inhibition of SREBP Improves Cardiac Lipidopathy, Improves Endoplasmic Reticulum Stress, and Modulates Chronic Chagas Cardiomyopathy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets