Universität zu Köln

Kasikara, Canan, Schilperoort, Maaike, Gerlach, Brennan, Xue, Chenyi, Wang, Xiaobo ORCID: 0000-0001-6044-914X, Zheng, Ze ORCID: 0000-0002-4453-224X, Kuriakose, George, Dorweiler, Bernhard, Zhang, Hanrui ORCID: 0000-0001-8655-938X, Fredman, Gabrielle, Saleheen, Danish, Reilly, Muredach P. and Tabas, Ira (2021). Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis. J. Clin. Invest., 131 (8). ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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Abstract

Efferocytosis, the process through which apoptotic cells (ACs) are cleared through actin-mediated engulfment by macrophages, prevents secondary necrosis, suppresses inflammation, and promotes resolution. Impaired efferocytosis drives the formation of clinically dangerous necrotic atherosclerotic plaques, the underlying etiology of coronary artery disease (CAD). An intron of the gene encoding PHACTR1 contains rs9349379 (A>G), a common variant associated with CAD. As PHACTR1 is an actin binding protein, we reasoned that if the rs9349379 risk allele G causes lower PHACTR1 expression in macrophages, it might link the risk allele to CAD via impaired efferocytosis. We show here that rs9349379-G/G was associated with lower levels of PHACTR1 and impaired efferocytosis in human monocyte-derived macrophages and human atherosclerotic lesional macrophages compared with rs9349379-A/A. Silencing PHACTR1 in human and mouse macrophages compromised AC engulfment, and Western diet-fed Ldlr-/- mice in which hematopoietic Phactr1 was genetically targeted showed impaired lesional efferocytosis, increased plaque necrosis, and thinner fibrous caps - all signs of vulnerable plaques in humans. Mechanistically, PHACTR1 prevented dephosphorylation of myosin light chain (MLC), which was necessary for AC engulfment. In summary, rs9349379-G lowered PHACTR1, which, by lowering phospho-MLC, compromised efferocytosis. Thus, rs9349379-G may contribute to CAD risk, at least in part, by impairing atherosclerotic lesional macrophage efferocytosis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kasikara, Canan UNSPECIFIED UNSPECIFIED UNSPECIFIED Schilperoort, Maaike UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerlach, Brennan UNSPECIFIED UNSPECIFIED UNSPECIFIED Xue, Chenyi UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Xiaobo UNSPECIFIED orcid.org/0000-0001-6044-914X UNSPECIFIED Zheng, Ze UNSPECIFIED orcid.org/0000-0002-4453-224X UNSPECIFIED Kuriakose, George UNSPECIFIED UNSPECIFIED UNSPECIFIED Dorweiler, Bernhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Hanrui UNSPECIFIED orcid.org/0000-0001-8655-938X UNSPECIFIED Fredman, Gabrielle UNSPECIFIED UNSPECIFIED UNSPECIFIED Saleheen, Danish UNSPECIFIED UNSPECIFIED UNSPECIFIED Reilly, Muredach P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tabas, Ira UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-589231
DOI:	10.1172/JCI145275
Journal or Publication Title:	J. Clin. Invest.
Volume:	131
Number:	8
Date:	2021
Publisher:	AMER SOC CLINICAL INVESTIGATION INC
Place of Publication:	ANN ARBOR
ISSN:	1558-8238
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENOME-WIDE ASSOCIATION; PROTEIN PHOSPHATASE-1; MYOCARDIAL INFARCTION; MYOSIN PHOSPHATASE; APOPTOTIC CELLS; CORONARY; LOCI; GENE; EXPRESSION; BINDING Multiple languages Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58923