DPP-4 inhibition by linagliptin prevents cardiac dysfunction and inflammation by targeting the Nlrp3/ASC inflammasome.
Basic Res Cardiol
; 114(5): 35, 2019 08 06.
Article
em En
| MEDLINE
| ID: mdl-31388770
ABSTRACT
We compared the effects of linagliptin (Lina, a DPP4 inhibitor) and GLP-1 receptor activation by exenatide followed by exendin-4 in an infusion pump (EX) on infarct size (IS), post-infarction activation of the inflammasome and remodeling in wild-type (WT) and db/db diabetic mice. Mice underwent 30 min ischemia followed by 24 h reperfusion. IS was assessed by TTC. Additional mice underwent permanent coronary artery occlusion. Echocardiography was performed 2w after infarction. Activation of the inflammasome in the border zone of the infarction was assessed by rt-PCR and ELISA 2w after reperfusion. Further in vitro experiments were done using primary human cardiofibroblasts and cardiomyocytes exposed to simulated ischemia-reoxygenation. Lina and EX limited IS in both the WT and the db/db mice. Lina and EX equally improved ejection fraction in both the WT and the db/db mice. mRNA levels of ASC, NALP3, IL-1ß, IL-6, Collagen-1, and Collagen-3 were higher in the db/db mice than in the WT mice. Infarction increased these levels in the WT and db/db mice. Lina more than EX attenuated the increase in ASC, NALP3, IL-1ß, IL-6, Collagen-1 and Collagen-3, TNFα and IL-1ß, and decreased apoptosis, especially in the db/db mice. In vitro experiments showed that Lina, but not EX, attenuated the increase in TLR4 expression, an effect that was dependent on p38 activation with downstream upregulation of Let-7i and miR-146b levels. Lina and EX had similar effects on IS and post-infarction function, but Lina attenuated the activation of the inflammasome and the upregulation of collagen-1 and collagen-3 more than direct GLP-1 receptor activation. This effect depends on p38 activation with downstream upregulation of miR-146b levels that suppresses TLR4 expression.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Diabetes Mellitus Tipo 2
/
Inibidores da Dipeptidil Peptidase IV
/
Inflamassomos
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Linagliptina
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Revista:
Basic Res Cardiol
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos