ER stress mediates Angiotensin II-augmented innate immunity memory and facilitates distinct susceptibilities of thoracic from abdominal aorta to aneurysm development

Abstract

To determine the roles of endoplasmic reticulum (ER) stress and trained immunity, we performed transcriptome analyses on the thoracic aorta (TA) and abdominal aorta (AA) from the angiotensin II (Ang II)-HFD-ApoE-KO aneurysm model and made significant findings: 1) Ang II bypassed HFD-induced metabolic reprogramming and induced stronger inflammation in AA than in TA; 2) Ang II and HFD upregulated 890 genes in AA versus TA and induced cytokine signaling; 3) Ang II AA and TA upregulated 73 and 68 cytokines, scRNA-Seq identified markers of macrophages and immune cells, cell death regulators, respectively; transdifferentiation markers of neuron, glial, and squamous epithelial cells were upregulated by Ang II-AA and TA; and pyroptosis signaling with IL-1β and caspase-4 were more upregulated in Ang II-AA than in TA; 4) Six upregulated transcriptomes in patients with AAA, Ang II AA, Ang II TA, additional aneurysm models, PPE-AAA and BAPN-Ang II-AAA, were partially overlapped with 10 lists of new ER stress gene sets including 3 interaction protein lists of ER stress regulators ATF6, PERK, and IRE1, HPA ER localization genes, KEGG signal genes, XBP1 transcription targets, ATF4 (PERK) targets, ATF6 targets, thapsigargin ER stress genes, tunicamycin-ER stress genes, respectively; 5) Ang II-AA and TA upregulated ROS regulators, MitoCarta genes, trained immunity genes, and glycolysis genes; and 6) Gene KO transcriptomes indicated that ATF6 and PERK played more significant roles than IRE1 in promoting AAA and trained immunity whereas antioxidant NRF2 inhibited them. Our unprecedented ER-focused transcriptomic analyses have provided novel insights on the roles of ER as an immune organelle in sensing various DAMPs and initiating ER stress that triggers Ang II-accelerated trained immunity and differs susceptibilities of thoracic and abdominal aortas to diseases.

Editorial: Debates in cardiovascular pharmacology and drug discovery: 2022

“…Each of these trained immunity types is characterized by specific mechanisms, including acetyl-CoA-cholesterol-driven histone acetylation dependence, S-adenosylhomocysteine (SAH) hypomethylationtriggered histone demethylation dependence, and glycolysisindependent metabolic pathways (2). These concurrent forms of trained immunity collectively play a pivotal role in exacerbating inflammation (13)(14)(15)(16)(17)(18)(19)(20) and driving the progression of atherosclerosis (2,21). In addition, this paper clearly showed that metabolomic reprogramming exhibits pronounced specificity at the tissue and subcellular organelle levels (22,23).…”

Trained Innate Immunity in Animal Models of Cardiovascular Diseases

“…But two recent animal studies and data analyses of animal studies provide at least evidence that TI could also be involved in the development and progression of aortic aneurysms [75,76]. One study found that ER stress and TI might play a role for thoracic or abdominal aortic aneurysms [75].…”

“…But two recent animal studies and data analyses of animal studies provide at least evidence that TI could also be involved in the development and progression of aortic aneurysms [75,76]. One study found that ER stress and TI might play a role for thoracic or abdominal aortic aneurysms [75]. For this, the authors utilized 9-10 weeks old apolipoprotein E-deficient (ApoE-/-) mice that were treated with angiotensin II (AngII, 1000 ng/kg/min) via aortic minipumps and in parallel fed with a HFD (2% cholesterol and 20% fat) for 28 days to foster the development of aortic aneurysms.…”

Innate immunity of vascular smooth muscle cells contributes to two-wave inflammation in atherosclerosis, twin-peak inflammation in aortic aneurysms and trans-differentiation potential into 25 cell types

“…Pathological findings indicated that AAAs have the features of vascular remodeling and the loss of VSMCs ( 30 ). Despite many progresses in determining the roles of genetic risk factors ( 31 ), inflammatory stimuli, inflammasome activation and pyroptosis ( 32 , 33 ), monocytes and macrophages ( 17 , 34 ), Tregs ( 35 ), cell death ( 36 ), reactive oxygen species (ROS) ( 37 – 39 ), matrix metalloproteinases (MMPs), microRNAs, circular RNAs ( 40 ) and epigenetics ( 38 ), VSMC phenotypic switching ( 13 ) and calcification ( 41 ), advanced technologies for gene discovery ( 31 ), and animal models ( 42 , 43 ), a significant question remains: which innate immune mechanisms are underlying the inflammatory signal amplification for the localized dilatations that happened in specific areas of the aorta ( 42 ).…”