Grant Renewal to Continue Work to Improve Vascular Function in People with Sickle Cell Disease Kirkwood A. Pritchard, Jr., PhD Professor, Division of Congenital Heart Surgery
Sickle Cell Disease Impairs Vascular Function by Inducing a Destructive Cycle. The destructive cycle starts with myeloperoxidase (MPO) released from activated neutrophils and other myeloid cells (Figure 1). MPO generates toxic oxidants that injure and kill the cells that makeup blood vessels. Dead and dying cells release high mobility group box-1 (HMGB1) from the cell’s nucleus which plays an essential role in maintaining DNA structure and regulating gene expression. However, when cells die, they passively release HMGB1 outside the cell, turning it into a potent inflammatory molecule that increases inflammation and recruitment of neutrophils to the vessel wall. After the neutrophils arrive, they bind to the endothelium lining the vessel wall and crawl into the vessel wall, where they become activated and cause even greater inflammation and tissue injury. Although all cells make HMGB1, even blood vessel
cells, when released from dead and dying cells, HMGB1 impairs the blood vessel’s ability to vasodilate, mediate blood flow, or repel activated neutrophils, damaged sickled RBC and activated platelets from the vessel wall. In this way, the MPO-HMGB1 destructive cycle increases vascular adhesion of neutrophils, RBC, and platelets. Our studies suggest the MPO-HMGB1 destructive cycle is a novel inflammatory pathway that sickle cell disease uses to injure the vessel wall and increase the risk of acute crises.
Current Therapies for Sickle Cell Disease Hydroxyurea, L-glutamine, oxbryta, and crizanlizumabtmca are currently the only therapies approved by the FDA for treating SCD. Hydroxyurea and L-glutamine reduce sickle crisis and vasocongestion. Hydroxyurea is a chemotherapeutic agent that reduces leukocyte counts and leukocyte-dependent inflammation. It also increases fetal Hb and decreases Hb polymerization. Finally, hydroxyurea even releases nitric oxide. Oral L-glutamine provides the energy that RBC use to metabolize oxidized lipids and reduce glutathione disulfide, thereby minimizing sickling and vasocongestion. Oxbryta inhibits hemoglobin S polymerization. Crizanlizumab-tmca binds to P-selectin on activated endothelial cells that line the blood vessel inner wall and circulating platelets to prevent adhesion of sickled red cells to the vessel wall. While all of these therapies help reduce vascular inflammation and RBC injury, sickling, and sticking to the vessel wall, none of these treatments target the mechanisms by which sickle cell disease induces vasculopathy as defined above in the destructive cycle (Figure 1). My laboratory designed and developed N-acetyllysyltyrosylcysteine amide (KYC), a first-in-class, multimodal, systems pharmacology agent for treating sickle cell disease. Unlike the FDAapproved drugs listed above, KYC inhibits the mechanisms Figure 1. Vasculopathy in Sickle Cell Disease is caused by a Destructive Cycle. 18 | Medical College of Wisconsin Department of Surgery
