Calcification Induced by Type I Interferon in Human Aortic Valve Interstitial Cells Is Larger in Males and Blunted by a Janus Kinase Inhibitor.

Abstract

Objective- Calcific aortic valve disease is the most prevalent valvulopathy in Western countries. An unanticipated pathogenetic clue involving IFN (interferon) was disclosed by the finding of constitutive type I IFN activity associated with aortic valve calcification in children with the atypical Singleton-Merten syndrome. On this basis, the role of type I IFN on inflammation and calcification in human aortic valve interstitial cells (AVIC) was examined. Approach and Results- IFN-α was weakly proinflammatory but potentiated lipopolysaccharide-mediated activation of NF (nuclear factor)-κB and the ensuing induction of proinflammatory molecules in human AVIC. Stimulation with IFN-α and in combination with lipopolysaccharide promoted osteoblast-like differentiation characterized by increased osteoblastic gene expression, BMP (bone morphogenetic protein)-2 secretion, and ectopic phosphatase activity. Sex differences were observed. Likewise, IFN-α treatment of human AVICs in osteogenic medium resulted in increased formation of calcific nodules. Strikingly, IFN-α-mediated calcification was significantly higher in AVICs from males, and was blocked by tofacitinib, a JAK (Janus kinase) inhibitor, and by a BMP antagonist. A female-specific protective mechanism involving the activation of PI3K-Akt (protein kinase B) pathways and cell survival was disclosed. Females exhibited higher levels of BCL2 in valve cells and tissues and lower annexin V staining on cell stimulation. Conclusions- IFN-α acts as a proinflammatory and pro-osteogenic cytokine in AVICs, its effects being potentiated by lipopolysaccharide. Results also uncovered sex differences with lower responses in female AVICs and sex-specific mechanisms involving apoptosis. Data point to JAK/STAT (signal transducer and activator of transcription) system as a potential therapeutic target for calcific aortic valve disease.

• Authors: Iván Parra-Izquierdo, Irene Castaños-Mollor, Javier López, Cristina Gómez, J Alberto San Román, Mariano Sánchez Crespo, Carmen García-Rodríguez
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 38 Issue 9 Pg. 2148-2159 (09 2018) ISSN: 1524-4636 [Electronic] United States
• PMID: 30026273 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BMP2 protein, human
• Bone Morphogenetic Protein 2
• Cytokines
• Interferon Type I
• Janus Kinase Inhibitors
• Lipopolysaccharides
• NF-kappa B
• Piperidines
• Pyrimidines
• Pyrroles
• STAT Transcription Factors
• Toll-Like Receptor 4
• tofacitinib
• Proto-Oncogene Proteins c-akt

Topics

• Aortic Valve (cytology, metabolism, pathology)
• Aortic Valve Stenosis (metabolism, pathology)
• Apoptosis
• Bone Morphogenetic Protein 2 (antagonists & inhibitors, metabolism)
• Calcinosis (metabolism, pathology)
• Cell Differentiation
• Cells, Cultured
• Cytokines (metabolism)
• Female
• Humans
• Interferon Type I (drug effects, metabolism)
• Janus Kinase Inhibitors (pharmacology)
• Lipopolysaccharides (pharmacology)
• Male
• NF-kappa B (metabolism)
• Osteoblasts (physiology)
• Piperidines (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)
• STAT Transcription Factors (metabolism)
• Sex Factors
• Signal Transduction
• Toll-Like Receptor 4 (metabolism)