Understanding Sickle Cell Cardiomyopathy

Sickle cell disease (SCD) is an inherited disorder of red blood cells caused by a point mutation in the beta-globin chain, leading to the formation of sickle-shaped erythrocytes. One of the leading causes of sudden death in young adult patients with SCD is cardiovascular disease, which pathogenesis is only partially elucidated. Here, we study the effect of aging on sickle cell-related cardiomyopathy. In SCD mice, we observed age-dependent cardiomegaly, associated with myocar-diocyte loss and degradation of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a), a key system in cardiomyocyte homeostasis. The increased activity of MMP9 is involved in the degradation of SERCA2a, suggesting a possible pro-inflammatory and pro-fibrotic environment characterizing the hearts from SCD mice. Indeed, we found increased collagen deposition associated with activation of TGF-β1 signaling pathways, with subsequent pathological myocardial remod-eling cascade. This was associated with activation of NF-kB, an inflammatory and redox-related transcriptional factor, and up-regulation of markers of inflammatory vasculopathy. Along with these data, we found heart infiltration of the lymphocyte subpopulation of Th17, which is linked to both pro-inflammatory cytokines (CCL2, CCXL2, IL17) and activation of the TGF-b1 pathway, contributing to the progres-sion of heart fibrosis. Since the therapeutic options to treat SCD and sickle cell organ complications are still limited, we investigated the effects of colchicine (0.1 mg/Kg/day) an anti-inflammatory and immune-modulatory drug, recently tested in different models of heart diseases. Colchicine-treated SCD mice showed (i) lower heart NFkB activa-tion, (ii) reduced cardiac Th17 infiltration, (iii) decrease pro-inflammatory and pro-fibrotic cytokines (iv) reduced activation of TGF-b1system and remodeling path-ways. In conclusion, our data contribute to going behind the state of the art and gen-erating the rationale to consider transferring colchicine to clinical trials as a new therapeutic option to prevent/limit sickle cell-related cardiomyopathy.