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

• DOI: 10.1096/fasebj.2018.32.1_supplement.676.13
• Publication Date: 2021-06-21T16:41:39Z
• Authors: Hannah Song; Philip M. Keegan; Avery J. Denby; Alexus Clark; Jada Selma; Suhaas Anbazhakan; Edward A. Botchwey; Manu Platt
• Keywords: Cathepsin K; Cathepsin S

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 sickle anemia have increased stroke risk, but mechanisms underlying arterial vasculopathy not well defined. Previously, we shown that adhesion of peripheral mononuclear cells (PBMCs) from to human aortic endothelial (ECs) significantly active cathepsin K V enzymes compared wildtype PBMCs suggesting inflammatory contribute pathologic vascular remodeling. In this study, Townes humanized knock‐in transgenic mice were used test hypotheses decode developing cerebral pursue pharmaceutical intervention studies hamper Carotid arteries (SS genotype) showed elastic lamina fragmentation as early 3 weeks old heterozygous littermate controls (AS) quantified by higher elastin break numbers per artery (n=4, p<.05). addition, expression K, a powerful elastase, was in carotid SS measured immunostaining, detected aortas zymography confirming accelerated proteolytic degradation. To block upstream signaling reduce remodeling, c‐jun N‐terminal kinase (JNK) inhibited SP600125 daily intraperitoneal injections for 8 3‐week‐old age (3wk+8wk treatment) or 11‐week‐old (11wk+8wk treatment). We hypothesized inhibiting JNK/cathepsin pathway at earlier will prevent onset later age, might be able regress remodeling least halt progression fragmentation. Accordingly, injection reduced indicated perimeters younger age. This suggests due mediated JNK signaling, perhaps through proteolysis elastin, more importantly, occurs mice, demonstrating their utility mechanistic complications anemia. Support Funding Information AHA, NIH abstract Experimental Biology 2018 Meeting. There no full text article associated published The FASEB Journal .