Sickle Cell Anemia Mediates Carotid Artery Expansive Remodeling That Can Be Prevented by Inhibition of JNK (c-Jun N-Terminal Kinase)

• Authors: Hannah Song, Emory University; Philip M Keegan, Emory University; Suhaas Anbazhakan, Emory University; Christian P Rivera, Emory University; Yundi Feng, Peking University; Victor O Omojola, Emory University; Alexus A Clark, Emory University; Shuangyi Cai, Emory University; Jade Selma, Emory University; Rudolph L Gleason, Emory University; Edward Botchwey, Emory University; Yunlong Huo, Peking University; Wenchang Tan, Peking University; Manu Platt, Emory University
• Journal Title: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
• Volume: Volume 40, Number 5
• Publisher: LIPPINCOTT WILLIAMS & WILKINS | 2020-05-01, Pages 1220-1230
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1161/ATVBAHA.120.314045
• Subjects: Engineering, Biomedical
• Keywords: Science & Technology; Life Sciences & Biomedicine; Hematology; Peripheral Vascular Disease; Cardiovascular System & Cardiology; carotid arteries; collagen; compliance; elastin; hematology; CATHEPSIN-K; ENDOTHELIAL-CELLS; WAVE REFLECTIONS; MOUSE MODEL; V ACTIVITY; STROKE; DISEASE; STIFFNESS; CHILDREN; RISK

Abstract

Objective: Sickle cell anemia (SCA) causes chronic inflammation and multiorgan damage. Less understood are the arterial complications, most evident by increased strokes among children. Proteolytic mechanisms, biomechanical consequences, and pharmaceutical inhibitory strategies were studied in a mouse model to provide a platform for mechanistic and intervention studies of large artery damage due to sickle cell disease. Approach and Results: Townes humanized transgenic mouse model of SCA was used to test the hypothesis that elastic lamina and structural damage in carotid arteries increased with age and was accelerated in mice homozygous for SCA (sickle cell anemia homozygous genotype [SS]) due to inflammatory signaling pathways activating proteolytic enzymes. Elastic lamina fragmentation observed by 1 month in SS mice compared with heterozygous littermate controls (sickle cell trait heterozygous genotype [AS]). Positive immunostaining for cathepsin K, a powerful collagenase and elastase, confirmed accelerated proteolytic activity in SS carotids. Larger cross-sectional areas were quantified by magnetic resonance angiography and increased arterial compliance in SS carotids were also measured. Inhibiting JNK (c-jun N-terminal kinase) signaling with SP600125 significantly reduced cathepsin K expression, elastin fragmentation, and carotid artery perimeters in SS mice. By 5 months of age, continued medial thinning and collagen degradation was mitigated by treatment of SS mice with JNK inhibitor. Conclusions: Arterial remodeling due to SCA is mediated by JNK signaling, cathepsin proteolytic upregulation, and degradation of elastin and collagen. Demonstration in Townes mice establishes their utility for mechanistic studies of arterial vasculopathy, related complications, and therapeutic interventions for large artery damage due to SCA.