Reduced Expression Level of the Cyclic Adenosine Monophosphate Response Element–Binding Protein Contributes to Lung Aging

Abstract

Lung aging is associated with morphological and physiological changes in which alterations in transcription factors, including the cyclic adenosine monophosphate response element-binding protein (CREB), could play a role. We studied CREB in lung tissue from mice at different ages and in response to known age-related factors (e.g., cellular senescence and matrix modifications with advanced glycation end-products [AGEs]). Our study shows that protein but not mRNA levels of CREB are reduced in the lungs of old mice. CREB reduction was also observed in senescent human lung fibroblasts (WI-38, LuFi) and human lung epithelial cells (A549) cultured on AGE-modified collagen matrix. Reduction of CREB protein is partially based on pre- and posttranslational modifications as exhibited by an increase in the CREB-regulating microRNA 34b and CREB ubiquitination. Permanent down-regulation of CREB in lung cells impaired cell proliferation and viability and increased the number of cells with senescence-associated β-galactosidase activity. CREB down-regulation was accompanied by the reduced expression of 165 genes in WI-38 fibroblasts and A549 epithelial cells, of which 15 genes showed a reduced expression in lung tissues of old mice. The CREB-dependent reduction in RAB27A coding for the Ras-related protein Rab27A and IGFBP3 coding for the insulin-like growth factor-binding protein 3 has been confirmed for aged lung tissue, senescent fibroblasts, and lung epithelial cells on AGE-modified collagen. Our data demonstrate that the reduced protein expression of CREB might play a significant role in lung aging by modifying the transcription of RAB27A, IGFBP3, and other target genes.

A common variant in RAB27A gene is associated with fractional exhaled nitric oxide levels in adults

“…None of these factors could explain the difference for RAB27A locus effects between children and adults because the genetic association signal was mainly observed in non-smoker, non-asthmatic or non-atopic individuals. Instead, the specific effect of the RAB27A polymorphism on FeNO levels in adults might reflect a strong gene by age interaction, which would be consistent with several lines of evidence implicating RAB27A in age-related changes of bronchial airways [27, 28]. In that light, it is possible that the adult-specific association could be related to ageing process or other factors throughout life that might influence FeNO levels.…”

“…Pulmonary epithelium atrophy has been described in lungs of double knockout mice (Rab27a and Rab27b), and interestingly these morphologic changes were observed in aged mice only (over 12–18 months) [27]. Moreover, a reduced expression of RAB27A was found in old mouse lung tissue (25–31 months), as well as in human senescent lung fibroblasts and lung epithelial cells [28]. These observations are in agreement with the absence of association signal between FeNO levels and SNPs at the RAB27A locus in the EAGLE children cohorts.…”

<p>Glucocorticoid Receptor α Mediates Roflumilast’s Ability to Restore Dexamethasone Sensitivity in COPD</p>

“…CREB expression and activation in lungs are impaired with age, as they were reduced in adult compared to young mice, and further decreased in old vs. adult animals. 39 As COPD is considered a disease of accelerated lung aging, 40,41 our findings imply that any such impairment may also conceivably contribute to COPD-associated GRα downregulation.…”

miRNome Profiling Detects miR-101-3p and miR-142-5p as Putative Blood Biomarkers of Frailty Syndrome

“…CREB1, CAMP responsive element binding protein 1, is a protein that binds the cAMP response element and regulates transcription. Its expression and function can modulate oxidative stress-induced senescence in granulosa cells by reducing the mitochondrial function [ 85 ] and CREB signaling has been related to lung and brain aging [ 86 , 87 ]. Finally, EIF5A2 encoding for the Eukaryotic Initiation Factor 5A2, plays a key role in the regulation of protein translation, and it has been reported that, in transgenic mice, its overexpression enhances the aging process [ 88 ].…”