Deletion of the NR4A nuclear receptor NOR1 in hematopoietic stem cells reduces inflammation but not abdominal aortic aneurysm formation

Hua Qing,Dennis Bruemmer,Hong Lu,Elizabeth B Heywood,Karrie L Jones,Alan Daugherty

doi:10.1186/s12872-017-0701-4

Abstract

BackgroundThe NR4A3 orphan nuclear hormone receptor, NOR1, functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling. Inflammatory processes represent key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NOR1 in AAA formation has not been investigated previously.MethodsInflammatory gene expression was analyzed in bone marrow-derived macrophages isolated from NOR1-deficient mice. Low-density lipoprotein receptor-deficient (LDLr−/−) mice were irradiated and reconstituted with hematopoietic stem cells obtained from NOR1−/− or wild-type littermate mice. Animals were infused with angiotensin II and fed a diet enriched in saturated fat to induce AAA formation. Quantification of AAA formation was performed by ultrasound and ex vivo measurements.ResultsAmong 184 inflammatory genes that were analyzed, 36 genes were differentially regulated in LPS-treated NOR1-deficient macrophages. Albeit this difference in gene regulation, NOR1-deficiency in hematopoietic stem cells did not affect development of AAA formation in bone marrow-derived stem cell transplanted LDLr-deficient mice.ConclusionNOR1 deletion induced differential inflammatory gene transcription in macrophages but did not influence AAA formation in mice.

Highlights

The NR4A3 orphan nuclear hormone receptor, Neuron-derived orphan receptor 1 (NOR1), functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling
Qing et al BMC Cardiovascular Disorders (2017) 17:271 is highly expressed in human abdominal aortic aneurysm tissues [7] and has been implicated previously in proliferation of myeloid progenitor cells [8, 9], recruitment of monocytes to sites of inflammation [10], transcription of inflammatory gene expression [11, 12], and macrophage apoptosis [13]. Based on this key function of NOR1 in the control of inflammation combined with the well-established contribution of macrophage-induced inflammatory signaling to AAA formation [14, 15], we investigated whether NOR1 deletion affects development of AAA
Genetic NOR1 deletion altered inflammatory gene expression To first investigate the regulation of NOR1 in macrophages, we incubated Bone marrow-derived macrophages (BMDM) isolated from wild-type littermate and NOR1−/− mice with LPS

Summary

Introduction

The NR4A3 orphan nuclear hormone receptor, NOR1, functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling. Inflammatory processes represent key mechanisms leading to abdominal aortic aneurysm (AAA) formation. Abdominal aortic aneurysms (AAA) affect more than 1.1 million people in the United States and bear an 85% chance of death after rupture [1]. Medial infiltration of macrophages and the activation of inflammatory signaling represents the earliest histological change during the initiation of AAA formation [3, 4]. The NR4A subgroup of orphan nuclear receptors represents immediate-early response genes, which are expressed rapidly in response to inflammatory stimulation and control essential cellular functions in all processes of pathological vascular remodeling [5, 6].

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