Nuclear Receptor NR1D1 Regulates Abdominal Aortic Aneurysm Development by Targeting the Mitochondrial Tricarboxylic Acid Cycle Enzyme Aconitase-2

Abstract

Background: Metabolic disorder increases the risk of abdominal aortic aneurysm (AAA). NRs (nuclear receptors) have been increasingly recognized as important regulators of cell metabolism. However, the role of NRs in AAA development remains largely unknown. Methods: We analyzed the expression profile of the NR superfamily in AAA tissues and identified NR1D1 (NR subfamily 1 group D member 1) as the most highly upregulated NR in AAA tissues. To examine the role of NR1D1 in AAA formation, we used vascular smooth muscle cell (VSMC)–specific, endothelial cell–specific, and myeloid cell–specific conditional Nr1d1 knockout mice in both AngII (angiotensin II)– and CaPO 4 -induced AAA models. Results: Nr1d1 gene expression exhibited the highest fold change among all 49 NRs in AAA tissues, and NR1D1 protein was upregulated in both human and murine VSMCs from AAA tissues. The knockout of Nr1d1 in VSMCs but not endothelial cells and myeloid cells inhibited AAA formation in both AngII- and CaPO 4 -induced AAA models. Mechanistic studies identified ACO2 (aconitase-2), a key enzyme of the mitochondrial tricarboxylic acid cycle, as a direct target trans-repressed by NR1D1 that mediated the regulatory effects of NR1D1 on mitochondrial metabolism. NR1D1 deficiency restored the ACO2 dysregulation and mitochondrial dysfunction at the early stage of AngII infusion before AAA formation. Supplementation with αKG (α-ketoglutarate, a downstream metabolite of ACO2) was beneficial in preventing and treating AAA in mice in a manner that required NR1D1 in VSMCs. Conclusions: Our data define a previously unrecognized role of nuclear receptor NR1D1 in AAA pathogenesis and an undescribed NR1D1-ACO2 axis involved in regulating mitochondrial metabolism in VSMCs. It is important that our findings suggest αKG supplementation as an effective therapeutic approach for AAA treatment.

The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress

“…In addition, with increasing age, chondrocyte proliferation decreased, and mitochondrial senescence and dysfunction emerged, thereby increasing ROS production and the levels of fatty acids, glucose, and inflammation mediators and, eventually, cartilage damage [ 46 ]. α-KG is an essential metabolite of the mitochondrial TCA cycle that can regulate mitochondrial metabolism, antioxidation, and anti-inflammation [ [14] , [15] , [16] , [17] ], and its serum levels gradually decrease with age [ 30 ]. Accordingly, in the present study, we first quantified α-KG content in cartilage.…”

“…The tricarboxylic acid (TCA) cycle, also known as citric acid or Krebs cycle, occurs in the mitochondria in eukaryotes and regulates mitochondrial function and oxidative stress [ [14] , [15] , [16] , [17] ]. α-ketoglutarate (α-KG) is a key intermediate metabolite in the TCA cycle, also known as 2-oxoglutarate [ 18 ], which contributes to a variety of metabolic processes, including the biogenesis of numerous amino acids, nucleotide, lipid, and carnitine biosynthesis, and as a cofactor in numerous dioxygenases [ [19] , [20] , [21] , [22] ].…”

Response by Sun et al to Letter Regarding Article, “Nuclear Receptor NR1D1 Regulates Abdominal Aortic Aneurysm Development by Targeting the Mitochondrial Tricarboxylic Acid Cycle Enzyme Aconitase-2”

“…3 In our study, we found that the ACO2 protein is predominantly located in the cytoplasm/mitochondria of smooth muscle cells, and that nuclear receptor NR1D1 regulates mitochondrial metabolism and energy balance by targeting its downstream Aco2 promoter. 1 These findings support a crucial role of the mitochondrial TCA cycle in the pathogenesis of AAA. Whether NR1D1 acts as an nTCA enzyme transcription modifier to regulate AAA or other cardiovascular diseases is also intriguing and worth further investigation in future studies.…”

Apply pressure-strain loop to quantify myocardial work in pulmonary hypertension: A prospective cohort study

“…Categorical variables were expressed as numbers (percentage). Independent sample t -test or Mann-Whitney U test was used to compare variables between PH patients with controls, while Pearson’s Chi-Squared test or Fisher exact test to compare the categorical variables ( 15 ). PASPcal was adjusted for TAPSE, FAC, RAP, RAA, RV/LV, LVGLS and RVGLS by multiple linear regression, and Bland-Altman plot was used for agreement analysis.…”