Hemolysis Induced Induction of Matrix Metalloproteinases in Sickle Cell Disease

Sickle Cell Disease (SCD) is a monogenic disorder that impacts around 100,000 people in the United States and 20 million people worldwide. SCD is caused by a point mutation in the β-globin gene. SCD can lead to complications, such as hemolysis, vaso-occlusion, oxidative stress, organ injury, and erythrocyte sickling. Organ injury, specifically liver injury, is one of the main causes of mortality in SCD patients. Hemolysis induced accumulation of hemoglobin, heme and iron acts as potent damage associated molecular pattern (DAMP) and can cause chronic liver injury and inflammation. Previous studies in the lab have demonstrated exacerbated injury and inflammation in SCD liver. Chronic inflammation is known to activate matrix metalloproteinases (MMPs) which can then induce the expression of cytokines and chemokines. In this study, we examined the role of hemolysis-induced induction of MMPs using blood and liver samples from humanized townes SCD mouse model. Proteomic analysis using SCD mouse blood sample revealed increased expression of 8 MMPs in SCD mice following oxyhemoglobin treatment compared to their baseline expression. We next examined the mRNA expression of these MMPs in the liver by doing qRT-PCR. Interestingly, two MMPs- Steap3 and Timp3, showed significant upregulation in SCD mice liver compared to the littermate control, which positively correlated with hemolysis and the age of the mouse. Studies are currently underway to understand the role of Steap3 and Timp3 in hemolysis-induced chronic liver injury and their potential usage as novel biomarkers of hemolysis-induced chronic organ injury in SCD