piperidines and Aortic-Diseases

Mutations in DDX58 (DExD/H-box helicase 58), which encodes the cytoplasmic RNA sensor retinoic acid-inducible gene I (RIG-I), were recently identified in the rare autoimmune disease Singleton-Merten syndrome (SMS). We report the spontaneous development of psoriasis-like skin lesions as an SMS-like symptom in transgenic mice harboring one of the RIG-I SMS variants, E373A. Histological analysis revealed typical characteristics of psoriasis, including the abnormal proliferation and differentiation of keratinocytes leading to epidermal hyperplasia, and infiltrates consisting of neutrophils, dendritic cells and T cells. Levels of the IL-23/IL-17 immune axis cytokines were high in the skin lesions. Rag2-/- transgenic mice showed partial amelioration of the phenotype, with down-regulation of inflammatory cytokines, including IL-17A, suggesting the importance of lymphocytes for the pathogenesis similar to that of human psoriasis. Of note, IL-17A deficiency abolished the skin phenotype, and treatment using the JAK inhibitor tofacitinib not only prevented onset, but also improved the skin manifestations even after onset. Our study provides further evidence for the involvement of RIG-I activation in the onset and progression of psoriasis via type I interferon signaling and the IL-23/IL-17 axis.

Topics: Animals; Aortic Diseases; DEAD Box Protein 58; Dendritic Cells; Dental Enamel Hypoplasia; DNA-Binding Proteins; Epidermis; Hyperplasia; Interferon Type I; Interleukin-17; Interleukin-23 Subunit p19; Janus Kinase Inhibitors; Janus Kinases; Keratinocytes; Metacarpus; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscular Diseases; Neutrophils; Odontodysplasia; Osteoporosis; Piperidines; Psoriasis; Pyrimidines; T-Lymphocytes; Vascular Calcification

Mitochondrial reactive oxygen species (ROS) contribute to inflammation and vascular remodeling during atherosclerotic plaque formation. C57BL/6N (6N) and C57BL/6J (6J) mice display distinct mitochondrial redox balance due to the absence of nicotinamide nucleotide transhydrogenase (NNT) in 6J mice. We hypothesize that differential NNT expression between these animals alters plaque development.. 6N and 6J mice were treated with AAV8-PCSK9 (adeno-associated virus serotype 8/proprotein convertase subtilisin/kexin type 9) virus leading to hypercholesterolemia, increased low-density lipoprotein, and atherosclerosis in mice fed a high-fat diet (HFD). Mice were co-treated with the mitochondria-targeted superoxide dismutase mimetic MitoTEMPO to assess the contribution of mitochondrial ROS to atherosclerosis.. Baseline and HFD-induced vascular superoxide is increased in 6J compared to 6N mice. MitoTEMPO diminished superoxide in both groups demonstrating differential production of mitochondrial ROS among these strains. PCSK9 treatment and HFD led to similar increases in plasma lipids in both 6N and 6J mice. However, 6J animals displayed significantly higher levels of plaque formation. MitoTEMPO reduced plasma lipids but did not affect plaque formation in 6N mice. In contrast, MitoTEMPO surprisingly increased plaque formation in 6J mice.. These data indicate that loss of NNT increases vascular ROS production and exacerbates atherosclerotic plaque development.

Topics: Animals; Antioxidants; Aorta; Aortic Diseases; Atherosclerosis; Cholesterol; Disease Models, Animal; Genetic Predisposition to Disease; Hypercholesterolemia; Male; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondrial Proteins; NADP Transhydrogenase, AB-Specific; Organophosphorus Compounds; Phenotype; Piperidines; Plaque, Atherosclerotic; Proprotein Convertase 9; Superoxides; Time Factors

The reduced adiponectin levels are associated with atherosclerosis. Adiponectin exerts its functions by activating adiponectin receptor (AdipoR). Proprotein convertase subtilisin kexin type 9 (PCSK9) degrades LDLR protein (low-density lipoprotein receptor) to increase serum LDL-cholesterol levels. PCSK9 expression can be regulated by PPARγ (peroxisome proliferator-activated receptor γ) or SREBP2 (sterol regulatory element-binding protein 2). The effects of AdipoR agonists on PCSK9 and LDLR expression, serum lipid profiles, and atherosclerosis remain unknown.. At cellular levels, AdipoR agonists (ADP355 and AdipoRon) induced PCSK9 transcription/expression that solely depended on activation of PPAR-responsive element in the PCSK9 promoter. AdipoR agonists induced PPARγ expression; thus, the AdipoR agonist-activated PCSK9 expression/production was impaired in PPARγ deficient hepatocytes. Meanwhile, AdipoR agonists transcriptionally activated LDLR expression by activating SRE in the LDLR promoter. Moreover, AMP-activated protein kinase α (AMPKα) was involved in AdipoR agonist-activated PCSK9 expression. In wild-type mice, ADP355 increased PCSK9 and LDLR expression and serum PCSK9 levels, which was associated with activation of PPARγ, AMPKα and SREBP2 and reduction of LDL-cholesterol levels. In contrast, ADP355 reduced PCSK9 expression/secretion in apoE-deficient (apoE. Our study demonstrates that AdipoR activation by agonists regulated PCSK9 expression differently in wild-type and apoE

Topics: AMP-Activated Protein Kinases; Animals; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Biomarkers; Cholesterol, LDL; Disease Models, Animal; Dose-Response Relationship, Drug; Genetic Predisposition to Disease; Hep G2 Cells; Humans; Hypolipidemic Agents; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Oligopeptides; Phenotype; Piperidines; Plaque, Atherosclerotic; PPAR gamma; Proprotein Convertase 9; Receptors, Adiponectin; Receptors, LDL; Response Elements; RNA Interference; Signal Transduction; Sterol Regulatory Element Binding Protein 2; Transcriptional Activation; Transfection; Up-Regulation