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.
Highlights
Aging is associated with an overall decline in lung function, changes in lung physiology, and an increased susceptibility to diseases [1]
As aging has been linked to the development of several lung diseases, understanding the underlying molecular and cellular mechanisms of aging is a pre-requisite for developing novel therapeutics for age-related lung diseases including, but not limited to chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), lung fibrosis, and lung cancer
There is alteration in the structure and content of cardiolipin leading to mitochondrial dysfunction [13]
Summary
Aging is associated with an overall decline in lung function, changes in lung physiology, and an increased susceptibility to diseases [1]. Lung injury and inflammation are associated with the aging process and are observed during acute lung injury (ALI) [2]. The process of normal physiological aging leads to enlarged alveolar spaces and loss of lung elasticity [3]. A combination of both intrinsic factors, such as agedependent gene changes, and extrinsic factors, such as epigenetics and environmental stress, increase susceptibility to lung diseases [4]. Some of the ageassociated features include increased oxidative stress, commonly in the form of reactive oxygen species (ROS, accumulation), alteration in the extracellular matrix (ECM), decreased production of anti-aging molecules, reduced antioxidant response, autophagy, and defective mitochondria [1, 4,5,6]
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