Session: 113. Hemoglobinopathies, Excluding Thalassemia: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Sickle Cell Disease, Translational Research, Hemoglobinopathies, Diseases, Biological Processes, pathogenesis
Here, we studied male and female humanized sickle cell mice (Hbatm1(HBA)Tow Hbbtm2(HBG1,HBB*)Tow) and healthy control (Hbatm1(HBA)Tow Hbbtm3(HBG1,HBB)Tow) at two different ages: a)young mice (3-4 months old); and b) old mice (7-8 months old), with 5-6 mice assigned to each group.
SCD mice developed an age-dependent cardiomyopathy, characterized by myocardiocyte loss and degradation of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a), a key system in cardiomyocyte homeostasis. This change was associated with overactivation of MMP9, which participates to both degradation of SERCA2a and to local pro-inflammatory and extracellular matrix remodeling, activation of NF-kB, an inflammatory and redox related transcriptional factor, and up-regulation of other markers of inflammatory vasculopathy, such as Endothelin 1 (ET-1) and P-Selectin. Histopathological studies showed heart infiltration by a Th17 lymphocyte subpopulation, which is linked to both pro-inflammatory cytokines (CCL2, CCXL2, IL17) and activation of TGF-b1 pathway, contributing to the progression of heart fibrosis, as supported by heart collagen deposition in SCD mice when compared to health controls.
Recent evidence indicates colchicine as a new therapeutic option for different cardiovascular diseases such as myocarditis, acute myocardial infarction, or pericarditis. Here, we evaluated the impact of colchicine (0.1 mg/Kg/day for 4 months by gavage, starting at 3 months of age, n=5-6 mice in each group) on sickle cell related murine cardiomyopathy compared to vehicle treated animals. In SCD mice colchicine (i) decreased pro-inflammatory and pro-fibrotic cytokines such as IL17 (Figure 1A); (ii) reduced heart Th17 infiltration (Figure 1B); (iii) prevented heart NF-kB activation; and (iv) reduced the activation of TGF-b1 system and myocardial remodeling pathways (Figure 1C).
Our data suggest that colchicine could be considered in SCD as new therapeutic option to prevent/limit SCD-related cardiomyopathy.
Disclosures: Ghigo: Kither Biotech: Current equity holder in private company. Pinto: Agios: Membership on an entity's Board of Directors or advisory committees; Biovalley: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Forni: BMS (Celgene): Consultancy, Research Funding, Speakers Bureau; Vertex: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.
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