Inhibition of extracellular cyclophilins with cyclosporine analog and development of atherosclerosis in apolipoprotein E-deficient mice

The Journal of Pharmacology and Experimental Therapeutics
Michael DitiatkovskiDmitri Sviridov

Abstract

Cyclophilins exert both intracellular and extracellular activities related to immune responses and inflammation, which have been implicated in pathogenesis of atherosclerosis. Pan-inhibition of cyclophilins has both pro- and antiatherosclerotic properties, but specific contributions of extracellular and intracellular cyclophilins to these effects have not been characterized. Here, using selective inhibitor of extracellular cyclophilins, we investigated the role of these molecules in atherosclerosis. Apolipoprotein E-null mice fed a high-fat diet received intraperitoneal injections every second day of either vehicle or two analogs of cyclosporine A (CsA): [Melle](4)-CsA (NIM811), a nonimmunosupressive cell-permeable inhibitor of both intracellular and extracellular cyclophilins; and [(4R)-4-[(6-carboxy-1H-benzo[d]imidazol-2-yl)-methyl]-4-methyl-l-threonine](1)-CsA (MM284), cell-impermeable analog only inhibiting extracellular cyclophilins. Development of atherosclerosis and composition of plaques in aorta and innominate artery were studied. Both analogs increased abundance and cross-sectional size of the atherosclerotic plaques in aorta but did not affect development of atherosclerosis in innominate artery. Neither compound affe...Continue Reading

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Citations

Jan 23, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Xiaolei WangJiajun Zhao
Jun 23, 2019·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Iryna VoloshynaAllison B Reiss
Jan 31, 2020·Oxidative Medicine and Cellular Longevity·Xiaolei WangJiajun Zhao

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