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Elastic lamina fragmentation in sickle mice can be rescued by JNK‐Cathepsin inhibition

Sickle cell disease (SCD) is the most common inherited blood disorder, affecting 100,000 people domestically, and an additional 300,000 babies with SCD are born globally each year. Children with sickle cell anemia have increased stroke risk, but mechanisms underlying arterial vasculopathy are not well defined. Previously, we have shown that adhesion of peripheral blood mononuclear cells (PBMCs) from people with SCD to human aortic endothelial cells (ECs) significantly increased active cathepsin K and V enzymes compared to wildtype PBMCs suggesting that inflammatory cells from SCD contribute to pathologic vascular remodeling. In this study, Townes humanized knock‐in sickle transgenic mice were used to test the hypotheses to decode mechanisms developing cerebral vasculopathy and to pursue pharmaceutical intervention studies to hamper vascular remodeling. Carotid arteries from sickle mice (SS genotype) showed elastic lamina fragmentation as early as 3 weeks old compared to heterozygous littermate controls (AS) quantified by significantly higher elastin break numbers per artery (n=4, p<.05). In addition, expression of cathepsin K, a powerful elastase, was increased in carotid arteries in SS mice measured by immunostaining, and active cathepsin K and V were detected in aortas of SS mice by zymography confirming accelerated proteolytic degradation. To block upstream signaling to cathepsin K and reduce elastin fragmentation and arterial remodeling, c‐jun N‐terminal kinase (JNK) was inhibited with SP600125 by daily intraperitoneal injections for 8 weeks from 3‐week‐old age (3wk+8wk treatment) or from 11‐week‐old (11wk+8wk treatment). We hypothesized that inhibiting JNK/cathepsin pathway at earlier age will prevent the onset of arterial remodeling, and at later age, we might be able to regress the arterial remodeling or at least to halt the progression of elastin fragmentation. Accordingly, SP600125 injection significantly reduced carotid arterial remodeling indicated by elastin fragmentation and artery perimeters in SS mice at younger age. This suggests that arterial remodeling due to sickle cell anemia is mediated by JNK signaling, perhaps through cathepsin K proteolysis of elastin, and more importantly, that this occurs in Townes SS mice, demonstrating their utility for mechanistic studies of arterial vasculopathy and complications due to sickle cell anemia.