Olivier Herbin1, Adam G Regelmann1, Bhama Ramkhelawon1, Erica G Weinstein1, Kathryn J Moore1, Konstantina Alexandropoulos2. 1. From the Icahn School of Medicine at Mount Sinai, Department of Medicine, The Immunology Institute, New York (O.H., E.G.W., K.A.); Quartzy, Inc, Palo Alto, CA (A.G.R.); and Leon H. Charney Division of Cardiology, Department of Medicine, NYU School of Medicine, New York (B.R., K.J.M.). 2. From the Icahn School of Medicine at Mount Sinai, Department of Medicine, The Immunology Institute, New York (O.H., E.G.W., K.A.); Quartzy, Inc, Palo Alto, CA (A.G.R.); and Leon H. Charney Division of Cardiology, Department of Medicine, NYU School of Medicine, New York (B.R., K.J.M.). k.alexandropoulos@mssm.edu.
Abstract
OBJECTIVE: The chronic inflammation associated with atherosclerosis is caused by lipid deposition followed by leukocyte recruitment to the arterial wall. We previously showed that the hematopoietic cell-specific adaptor protein Cas- and Hef1-associated signal transducer hematopoietic isoform (Chat-H)/SHEP1 regulated lymphocyte adhesion and migration. In this study, we analyzed the role of Chat-H in atherosclerosis development. APPROACH AND RESULTS: Using Chat-H-deficient bone marrow transplantation in low-density lipoprotein receptor-deficient mice, we found that Chat-H regulated atherosclerotic plaque formation. Chat-H deficiency in hematopoietic cells associated with lower plaque complexity and fewer leukocytes in the lesions, whereas myeloid-specific deletion of Chat-H was sufficient for conferring atheroprotection. Chat-H deficiency resulted in reduced recruitment of classical Ly6c(high) and nonclassical Ly6c(low) monocytes to the plaques, which was accompanied by increased numbers of both monocyte subsets in the blood. This associated with defective adhesion of Chat-H-deficient Ly6c(high) and Ly6c(low) monocytes to vascular cell adhesion molecule-1 in vitro and impaired infiltration of fluorescent bead-loaded monocytes to atherosclerotic plaques. In contrast, Chat-H was dispensable for CX3CL1 and CCR1/CCR5-dependent migration of monocytes. CONCLUSIONS: Our findings highlight Chat-H as a key protein that regulates atherosclerosis development by controlling monocyte adhesion and recruitment to the plaques and identify a novel target that may be exploited for treating atherosclerosis.
OBJECTIVE: The chronic inflammation associated with atherosclerosis is caused by lipid deposition followed by leukocyte recruitment to the arterial wall. We previously showed that the hematopoietic cell-specific adaptor protein Cas- and Hef1-associated signal transducer hematopoietic isoform (Chat-H)/SHEP1 regulated lymphocyte adhesion and migration. In this study, we analyzed the role of Chat-H in atherosclerosis development. APPROACH AND RESULTS: Using Chat-H-deficient bone marrow transplantation in low-density lipoprotein receptor-deficient mice, we found that Chat-H regulated atherosclerotic plaque formation. Chat-H deficiency in hematopoietic cells associated with lower plaque complexity and fewer leukocytes in the lesions, whereas myeloid-specific deletion of Chat-H was sufficient for conferring atheroprotection. Chat-H deficiency resulted in reduced recruitment of classical Ly6c(high) and nonclassical Ly6c(low) monocytes to the plaques, which was accompanied by increased numbers of both monocyte subsets in the blood. This associated with defective adhesion of Chat-H-deficient Ly6c(high) and Ly6c(low) monocytes to vascular cell adhesion molecule-1 in vitro and impaired infiltration of fluorescent bead-loaded monocytes to atherosclerotic plaques. In contrast, Chat-H was dispensable for CX3CL1 and CCR1/CCR5-dependent migration of monocytes. CONCLUSIONS: Our findings highlight Chat-H as a key protein that regulates atherosclerosis development by controlling monocyte adhesion and recruitment to the plaques and identify a novel target that may be exploited for treating atherosclerosis.
Authors: Filip K Swirski; Peter Libby; Elena Aikawa; Pilar Alcaide; F William Luscinskas; Ralph Weissleder; Mikael J Pittet Journal: J Clin Invest Date: 2007-01 Impact factor: 14.808
Authors: Maik Drechsler; Remco T A Megens; Marc van Zandvoort; Christian Weber; Oliver Soehnlein Journal: Circulation Date: 2010-10-18 Impact factor: 29.690
Authors: Clinton S Robbins; Ingo Hilgendorf; Georg F Weber; Igor Theurl; Yoshiko Iwamoto; Jose-Luiz Figueiredo; Rostic Gorbatov; Galina K Sukhova; Louisa M S Gerhardt; David Smyth; Caleb C J Zavitz; Eric A Shikatani; Michael Parsons; Nico van Rooijen; Herbert Y Lin; Mansoor Husain; Peter Libby; Matthias Nahrendorf; Ralph Weissleder; Filip K Swirski Journal: Nat Med Date: 2013-08-11 Impact factor: 53.440
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
Authors: Laurienne Edgar; Naveed Akbar; Adam T Braithwaite; Thomas Krausgruber; Héctor Gallart-Ayala; Jade Bailey; Alastair L Corbin; Tariq E Khoyratty; Joshua T Chai; Mohammad Alkhalil; André F Rendeiro; Klemen Ziberna; Ritu Arya; Thomas J Cahill; Christoph Bock; Jurga Laurencikiene; Mark J Crabtree; Madeleine E Lemieux; Niels P Riksen; Mihai G Netea; Craig E Wheelock; Keith M Channon; Mikael Rydén; Irina A Udalova; Ricardo Carnicer; Robin P Choudhury Journal: Circulation Date: 2021-07-13 Impact factor: 29.690