Global gene profiling of aging lungs in Atp8b1 mutant mice

Abstract

ObjectiveRecent studies implicate cardiolipin oxidation in several age-related diseases. Atp8b1 encoding Type 4 P-type ATPases is a cardiolipin transporter. Mutation in Atp8b1 gene or inflammation of the lungs impairs the capacity of Atp8b1 to clear cardiolipin from lung fluid. However, the link between Atp8b1 mutation and age-related gene alteration is unknown. Therefore, we investigated how Atp8b1 mutation alters age-related genes.MethodsWe performed Affymetrix gene profiling of lungs isolated from young (7-9 wks, n=6) and aged (14 months, 14 M, n=6) C57BL/6 and Atp8b1 mutant mice. In addition, Ingenuity Pathway Analysis (IPA) was performed. Differentially expressed genes were validated by quantitative real-time PCR (qRT-PCR).ResultsGlobal transcriptome analysis revealed 532 differentially expressed genes in Atp8b1 lungs, 157 differentially expressed genes in C57BL/6 lungs, and 37 overlapping genes. IPA of age-related genes in Atp8b1 lungs showed enrichment of Xenobiotic metabolism and Nrf2-mediated signaling pathways. The increase in Adamts2 and Mmp13 transcripts in aged Atp8b1 lungs was validated by qRT-PCR. Similarly, the decrease in Col1a1 and increase in Cxcr6 transcripts was confirmed in both Atp8b1 mutant and C57BL/6 lungs.ConclusionBased on transcriptome profiling, our study indicates that Atp8b1 mutant mice may be susceptible to age-related lung diseases.

Cigarette Smoke Exposure and Inflammatory Signaling Increase the Expression of the SARS-CoV-2 Receptor ACE2 in the Respiratory Tract

“…We therefore investigated whether either feature was associated with increased ACE2 expression. In four different cohorts of aging mice and one cohort of aging rats, we did not detect a significant age-dependent change in ACE2 expression in the lung (Figures 1A, 1B, and S1D-S1F) (The Tabula Muris Consortium et al, Jonker et al, 2013;Misra et al, 2007;Soundararajan et al, 2016;Yu et al, 2014). Similarly, ACE2 expression in rodent lungs was not significantly different between sexes (Figures 1C and 1D) (Crowley et al, 2015;Yu et al, 2014).…”

Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung

“…Loss of Nrf2 expression can be a consequence of aging [9, 10], functional polymorphisms [11], and/or fibrotic TGF-β/pSmad3 signaling [12–15]. Preclinical models of pulmonary fibrosis indicate that Nrf2 is suppressed as the disease progresses [16, 17] and that haploinsufficiency is sufficient for enhanced susceptibility [8].…”

Mitochondrial biology in airway pathogenesis and the role of NRF2

“…Increased airway cardiolipin secretion and development of pneumonia were detected in type 2 cells of mice with a functional mutation (G308V) in a cardiolipin transporter (ATPase, aminophospholipid transporter, class I, type 8B, member 1, ATP8B1) (Ray et al 2010). In addition, decreased lung NRF2-ARE responses were found in the aged Atp8b1 mutant mice (14 month) compared to aged wildtype mice (Soundararajan et al 2016). Overall, these studies indicated that cardiolipin homeostasis may be protective in age-related lung disorders.…”