Targeting TLR4 with ApTOLL Improves Heart Function in Response to Coronary Ischemia Reperfusion in Pigs Undergoing Acute Myocardial Infarction.
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2020
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Biomolecules
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Abstract
Toll-like receptor 4 (TLR4) contributes to the pathogenesis of coronary ischemia/reperfusion
(IR). To test whether the new TLR4 antagonist, ApTOLL, may prevent coronary IR damage, we
administered 0.078 mg/kg ApTOLL or Placebo in pigs subjected to IR, analyzing the levels of cardiac
troponins, matrix metalloproteinases, pro-, and anti-inflammatory cytokines, heart function, and tissue
integrity over a period of 7 days after IR. Our results show that ApTOLL reduced cardiac troponin-1
24 h after administration, improving heart function, as detected by a significant recovery of the left
ventricle ejection fraction (LVEF) and the shortening fraction (FS) cardiac parameters. The extension
of necrotic and fibrotic areas was also reduced, as detected by Evans blue/2,3,5-triphenyltetrazolium
chloride (TTC) staining, Hematoxylin/Eosine, and Masson Trichrome staining of heart sections,
together with a significant reduction in the expression of the extracellular matrix-degrading, matrix
metalloproteinase 9. Finally, the expression of the following cytokines, CCL1, CCL2, MIP1-A-B,
CCL5, CD40L, C5/C5A, CXCL1, CXCL10, CXCL11, CXCL12, G-CSF, GM-CSF, ICAM-1, INF-g, IL1-a,
ILI-b, IL-1Ra, IL2, IL4, IL5, IL6, IL8, IL10, IL12, IL13, IL16, IL17-A, IL17- E, IL18, IL21, IL27, IL32,
MIF, SERPIN-E1, TNF-a, and TREM-1, were also assayed, detecting a pronounced decrease of
pro-inflammatory cytokines after 7 days of treatment with ApTOLL. Altogether, our results show
that ApTOLL is a promising new tool for the treatment of acute myocardial infarction (AMI).
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Keywords
Toll-like receptor 4, Acutemyocardial infarction, Cytokines, Matrixmetalloproteinases