α-Galactosylceramide and its analog OCH differentially affect the pathogenesis of ISO-induced cardiac injury in mice  

作　　者：Xin Chen Jie Liu Jie Liu Wen-jia Wang Wen-jing Lai Shu-hui Li Ya-fei Deng Jian-zhi Zhou Sheng-qian Yang Ying Liu Wei-nian Shou Da-yan Cao Xiao-hui Li 

机构地区：[1]Institute of Materia Medica and Center of Translational Medicine,College of Pharmacy,Army Medical University,Chongqing 400038,China [2]Department of Pharmacy,Xinqiao Hospital,Army Medical University,Chongqing 400037,China [3]Department of Clinical Biochemistry,College of Pharmacy,Army Medical University,Chongqing 400038,China [4]Hunan Children's Research Institute(HCRI),Hunan Children's Hospital,Changsha 410007,China [5]School of Medicine,Chongqing University,Chongqing 400016,China [6]Department of Pediatrics,Herman B Wells Center for Pediatric Research,Indiana University School of Medicine,Indianapolis,IN,USA

出　　处：《Acta Pharmacologica Sinica》2020年第11期1416-1426,共11页中国药理学报（英文版）

基　　金：This study was funded by the National Natural Science Foundation of China(#81773742 and #81520108029 to XHL,#81703521 to YFD,and #81473260 to JZZ).

摘　　要：Immunotherapies for can cers may cause severe and life-threate ning cardiotoxicities.The underlyi ng mecha nisms are complex and largely elusive.Currently,there are several on going clinical trials based on the use of activated in variant n atural killer T(iNKT)cells.The pote ntial cardiotoxicity commonly associated with this particular immuno therapy has yet bee n carefully evaluated.The prese nt study aims to determine the effect of activated iNKT cells on normal and p-adrenergic agonist(isoproterenol,ISO)-stimulated hearts.Mice were treated with iNKT stimulants,a-galactosylceramide(αGC)or its analog OCH,respectively,to determine their effect on ISO-induced cardiac injury.We showed that administration ofαGC(activating both T helper type 1(Th1)-and T helper type 2(Tlh2)-liked iNKT cells)significantly accelerated the progressive cardiac injury,leading to enhanced cardiac hypertrophy and cardiac fibrosis with promi nent in creases in collage n deposition and TGF-β1,IL-6,and alpha smooth muscle actin expressi on.In contrast toαGC,OCH(mainly activating Th2-liked iNKT cells)significantly attenuated the progression of cardiac injury and cardiac in flammation in duced by repeated infusion of ISO.Flow cytometry an alysis revealed thatαGC promoted inflammatory macrophage in filtration in the heart,while OCH was able to restrain the infiltration.In vitro coculture ofαGC-or OCH-pretreated primary peritoneal macrophages with primary cardiac fibroblasts confirmed the profibrotic effect ofαGC and the antifibrotic effect of OCH.Our results demonstrate that activating both Th1-and Th2-liked iNKT cells is cardiotoxic,while activating Th2-liked iNKT cells is likely cardiac protective,which has implied key differences among subpopulations of iNKT cells in their response to cardiac pathological stimulation.

关 键 词：α-galactosylceramide OCH iNKT cells isoprote renol can cer immunotherapy CARDIOTOXICITY on cocardiology 

分 类 号：R96[医药卫生—药理学]