Aksam Merched1, Katherine Tollefson, Lawrence Chan. 1. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, R630, Houston, TX 77030, USA. amerched@bcm.edu
Abstract
AIMS: Beta2 integrin-mediated adhesion is thought to be a key event in cardiovascular disease. However, results of clinical trials targeting these molecules have been disappointing. Here, we investigated the effect of inactivation of beta2 integrins at different stages of atherosclerosis by timed bone marrow transplantation (BMT) of CD18(-/-) cells in low-density lipoprotein receptor knockout (LDLR(-/-)) mice. METHODS AND RESULTS: Early BMT before fatty streak formation revealed a short-term protective effect of CD18 (34% atherosclerotic lesion reduction). Once fatty streak lesions had developed (5-week atherogenic diet) before BMT, beta2 integrin expression did not affect lesion progression. However, after the establishment of more mature lesions (pre-feeding mice the atherogenic diet for 10 weeks), CD18(+/+) BMT enhanced atherosclerosis (36%) lesion progression compared with CD18(-/-) BMT. Furthermore, beta2 integrins modulated the capacity of isolated peritoneal macrophages to take up acetylated LDL and native LDL and to phagocytose apoptotic cells, possibly via CD18-dependent mitogen-activated protein kinase signalling. Gene expression profile of CD18(-/-) and CD18(+/+) macrophages revealed significant differences in putative protective as well as atherogenic functions. CONCLUSION: beta2 integrin-mediated interaction between leucocytes and the vessel wall is a time-dependent and dynamic process. During the initiation phase, it protects against atherosclerotic lesion formation. However, with the evolution of the lesion and chronic exposure to dyslipidaemia, beta2 integrins' pro-atherogenic action becomes dominant, accelerating the atherosclerotic process.
AIMS: Beta2 integrin-mediated adhesion is thought to be a key event in cardiovascular disease. However, results of clinical trials targeting these molecules have been disappointing. Here, we investigated the effect of inactivation of beta2 integrins at different stages of atherosclerosis by timed bone marrow transplantation (BMT) of CD18(-/-) cells in low-density lipoprotein receptor knockout (LDLR(-/-)) mice. METHODS AND RESULTS: Early BMT before fatty streak formation revealed a short-term protective effect of CD18 (34% atherosclerotic lesion reduction). Once fatty streak lesions had developed (5-week atherogenic diet) before BMT, beta2 integrin expression did not affect lesion progression. However, after the establishment of more mature lesions (pre-feeding mice the atherogenic diet for 10 weeks), CD18(+/+) BMT enhanced atherosclerosis (36%) lesion progression compared with CD18(-/-) BMT. Furthermore, beta2 integrins modulated the capacity of isolated peritoneal macrophages to take up acetylated LDL and native LDL and to phagocytose apoptotic cells, possibly via CD18-dependent mitogen-activated protein kinase signalling. Gene expression profile of CD18(-/-) and CD18(+/+) macrophages revealed significant differences in putative protective as well as atherogenic functions. CONCLUSION:beta2 integrin-mediated interaction between leucocytes and the vessel wall is a time-dependent and dynamic process. During the initiation phase, it protects against atherosclerotic lesion formation. However, with the evolution of the lesion and chronic exposure to dyslipidaemia, beta2 integrins' pro-atherogenic action becomes dominant, accelerating the atherosclerotic process.
Authors: Ariel Werman; Rachel Werman-Venkert; Rosalyn White; Jae-Kwon Lee; Batsheva Werman; Yakov Krelin; Elena Voronov; Charles A Dinarello; Ron N Apte Journal: Proc Natl Acad Sci U S A Date: 2004-02-24 Impact factor: 11.205
Authors: M F Nageh; E T Sandberg; K R Marotti; A H Lin; E P Melchior; D C Bullard; A L Beaudet Journal: Arterioscler Thromb Vasc Biol Date: 1997-08 Impact factor: 8.311
Authors: Moammir H Aziz; Kui Cui; Mitali Das; Kathleen E Brown; Christopher L Ardell; Maria Febbraio; Elzbieta Pluskota; Juying Han; Huaizhu Wu; Christie M Ballantyne; Jonathan D Smith; Martha K Cathcart; Valentin P Yakubenko Journal: J Immunol Date: 2017-05-12 Impact factor: 5.422
Authors: Nicole M Mackey-Lawrence; Xiaoti Guo; Daniel E Sturdevant; Kimmo Virtaneva; Matthew M Hernandez; Eric Houpt; Alan Sher; Stephen F Porcella; William A Petri Journal: Infect Immun Date: 2013-02-19 Impact factor: 3.441
Authors: Jaume Padilla; Nathan T Jenkins; Sewon Lee; Hanrui Zhang; Jian Cui; Mozow Y Zuidema; Cuihua Zhang; Michael A Hill; James W Perfield; Jamal A Ibdah; Frank W Booth; J Wade Davis; M Harold Laughlin; R Scott Rector Journal: Physiol Genomics Date: 2013-04-16 Impact factor: 3.107
Authors: Takeshi Fujisawa; Keqing Wang; Xi-Lin Niu; Stuart Egginton; Shakil Ahmad; Peter Hewett; Christopher D Kontos; Asif Ahmed Journal: Cardiovasc Res Date: 2017-01 Impact factor: 10.787