Colchicine Protects Against Cardiomyopathy in Humanized Mouse Model for Sickle Cell Disease

Abstract

Sickle cell disease (SCD) is a genetically determined hemolytic anemia with high mortality and morbidity. Sickle cell related cardiomyopathy is one of the main causes of death in adult patients with SCD. Although progress in the knowledge of SCD has been made in the last decade, the pathogenesis of sickle related cardiomyopathy is still under investigation. 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. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal