Your browser doesn't support javascript.
loading
Sickle Cell Anemia Mediates Carotid Artery Expansive Remodeling That Can Be Prevented by Inhibition of JNK (c-Jun N-Terminal Kinase).
Song, Hannah; Keegan, Philip M; Anbazhakan, Suhaas; Rivera, Christian P; Feng, Yundi; Omojola, Victor O; Clark, Alexus A; Cai, Shuangyi; Selma, Jada; Gleason, Rudolph L; Botchwey, Edward A; Huo, Yunlong; Tan, Wenchang; Platt, Manu O.
Afiliação
  • Song H; From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta (H.S., P.M.K., S.A., C.P.R., V.O.O., A.A.C., S.C., J.S., R.L.G., E.A.B., M.O.P.).
  • Keegan PM; From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta (H.S., P.M.K., S.A., C.P.R., V.O.O., A.A.C., S.C., J.S., R.L.G., E.A.B., M.O.P.).
  • Anbazhakan S; From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta (H.S., P.M.K., S.A., C.P.R., V.O.O., A.A.C., S.C., J.S., R.L.G., E.A.B., M.O.P.).
  • Rivera CP; From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta (H.S., P.M.K., S.A., C.P.R., V.O.O., A.A.C., S.C., J.S., R.L.G., E.A.B., M.O.P.).
  • Feng Y; Department of Mechanics and Engineering Science at Peking University, Beijing, China (C.P.R., Y.F., Y.H., W.T.).
  • Omojola VO; Department of Mechanics and Engineering Science at Peking University, Beijing, China (C.P.R., Y.F., Y.H., W.T.).
  • Clark AA; From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta (H.S., P.M.K., S.A., C.P.R., V.O.O., A.A.C., S.C., J.S., R.L.G., E.A.B., M.O.P.).
  • Cai S; From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta (H.S., P.M.K., S.A., C.P.R., V.O.O., A.A.C., S.C., J.S., R.L.G., E.A.B., M.O.P.).
  • Selma J; From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta (H.S., P.M.K., S.A., C.P.R., V.O.O., A.A.C., S.C., J.S., R.L.G., E.A.B., M.O.P.).
  • Gleason RL; From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta (H.S., P.M.K., S.A., C.P.R., V.O.O., A.A.C., S.C., J.S., R.L.G., E.A.B., M.O.P.).
  • Botchwey EA; From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta (H.S., P.M.K., S.A., C.P.R., V.O.O., A.A.C., S.C., J.S., R.L.G., E.A.B., M.O.P.).
  • Huo Y; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta (R.L.G., E.A.B., M.O.P.).
  • Tan W; From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta (H.S., P.M.K., S.A., C.P.R., V.O.O., A.A.C., S.C., J.S., R.L.G., E.A.B., M.O.P.).
  • Platt MO; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta (R.L.G., E.A.B., M.O.P.).
Arterioscler Thromb Vasc Biol ; 40(5): 1220-1230, 2020 05.
Article em En | MEDLINE | ID: mdl-32160775
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.
Assuntos
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Artérias Carótidas / Doenças das Artérias Carótidas / Proteínas Quinases JNK Ativadas por Mitógeno / Inibidores de Proteínas Quinases / Remodelação Vascular / Anemia Falciforme / Antracenos Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Artérias Carótidas / Doenças das Artérias Carótidas / Proteínas Quinases JNK Ativadas por Mitógeno / Inibidores de Proteínas Quinases / Remodelação Vascular / Anemia Falciforme / Antracenos Idioma: En Ano de publicação: 2020 Tipo de documento: Article