REM-Predominant Obstructive Sleep Apnea in Patients with Coronary Artery Disease.

Obstructive sleep apnea (OSA) is common in adults with coronary artery disease (CAD). OSA that occurs predominantly during rapid-eye movement (REM) sleep has been identified as a specific phenotype (REM-predominant OSA) in sleep clinic cohorts. We aimed to examine the association of REM-predominant OSA with excessive sleepiness, functional outcomes, mood, and quality of life in a CAD cohort, of whom 286 OSA patients with total sleep time ≥ 240 min, and REM sleep ≥ 30 min, were included. REM-predominant OSA was defined as a REM-apnea-hypopnea-index (AHI) /non-REM (NREM) AHI ≥ 2. In all, 73 (25.5%) had REM-predominant OSA. They were more likely to be female (26.0% vs. 9.9%; p = 0.001), and more obese (42.5% vs. 24.4%; p = 0.003) but had less severe OSA in terms of AHI (median 22.6/h vs. 36.6/h; p < 0.001) compared to the patients with non-stage specific OSA. In adjusted logistic regression models, female sex (odds ratio [OR] 4.64, 95% confidence interval [CI] 1.85−11.64), body-mass-index (BMI; OR 1.17; 95% CI 1.07−1.28) and AHI (OR 0.93, 95% CI 0.91−0.95) were associated with REM-predominant OSA. In univariate linear regression models, there was a dose-response relationship between REM-AHI and Zung Self-rated Depression Scale but not excessive sleepiness, functional outcomes, and anxiety scores. Among the Short Form-36 subdomains, Vitality, Mental Health, and Mental Component Summary (MCS) scores were inversely correlated with REM-AHI. In multivariate linear models, only MCS remained significantly associated with REM-AHI after adjustment for age, BMI, and sex (ß-coefficient −2.20, %95 CI [−0.56, −0.03]; p = 0.028). To conclude, female sex and BMI were related to REM-predominant OSA in this revascularized cohort. MCS was inversely associated with REM-AHI in the multivariate model.

A nonaggregating surfactant protein C mutant is misdirected to early endosomes and disrupts phospholipid recycling.

Interstitial lung disease in both children and adults has been linked to mutations in the lung-specific surfactant protein C (SFTPC) gene. Among these, the missense mutation [isoleucine to threonine at codon 73 = human surfactant protein C (hSP-C(I73T) )] accounts for ∼30% of all described SFTPC mutations. We reported previously that unlike the BRICHOS misfolding SFTPC mutants, expression of hSP-C(I73T) induces lung remodeling and alveolar lipoproteinosis without a substantial Endoplasmic Reticulum (ER) stress response or ER-mediated intrinsic apoptosis. We show here that, in contrast to its wild-type counterpart that is directly routed to lysosomal-like organelles for processing, SP-C(I73T) is misdirected to the plasma membrane and subsequently internalized to the endocytic pathway via early endosomes, leading to the accumulation of abnormally processed proSP-C isoforms. Functionally, cells expressing hSP-C(I73T) demonstrated both impaired uptake and degradation of surfactant phospholipid, thus providing a molecular mechanism for the observed lipid accumulation in patients expressing hSP-C(I73T) through the disruption of normal phospholipid recycling. Our data provide evidence for a novel cellular mechanism for conformational protein-associated diseases and suggest a paradigm for mistargeted proteins involved in the disruption of the endosomal/lysosomal sorting machinery.

A novel conserved targeting motif found in ABCA transporters mediates trafficking to early post-Golgi compartments.

The ATP binding cassette, class A (ABCA) proteins are homologous polytopic transmembrane transporters that function as lipid pumps at distinct subcellular sites in a variety of cells. Located within the N terminus of these transporters, there exists a highly conserved xLxxKN motif of unknown function. To define its role, human ABCA3 was employed as a primary model representing ABCA transporters, while mouse ABCA1 was utilized to support major findings. Transfection studies showed colocalization of both transporters with surfactant protein C (SP-C), a marker peptide for successful protein targeting to lysosomal-like organelles. In contrast, alanine mutation of xLxxKN resulted in endoplasmic reticulum retention. As proof of principle, swapping xLxxKN for the known lysosomal targeting motif of SP-C resulted in post-Golgi targeting of the SP-C chimera. However, these products failed to reach their terminal processing compartments, suggesting that the xLxxKN motif only serves as a Golgi exit signal. We propose a model whereby an N-terminal signal sequence, xLxxKN, directs ABCA transporters to a post-Golgi vesicular sorting station where additional signals may be required for selective delivery of individual transporters to final subcellular destinations.

Misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- and cytochrome c-related mechanisms.

Several mutations within the BRICHOS domain of surfactant protein C (SP-C) have been linked to interstitial lung disease. Recent studies have suggested that these mutations cause misfolding of the proprotein (proSP-C), which initiates the unfolded protein response to resolve improper folding or promote protein degradation. We have reported that in vitro expression of one of these proteins, the exon 4 deletion mutant (hSP-C(Deltaexon4)), causes endoplasmic reticulum (ER) stress, inhibits proteasome function, and activates caspase-3-mediated apoptosis. To further elucidate mechanisms and common pathways for cellular dysfunction, various assays were performed by transiently expressing two SP-C BRICHOS domain mutant (BRISPC) proteins (hSP-C(Deltaexon4), hSP-C(L188Q)) and control proteins in lung epithelium-derived A549 and kidney epithelium-derived (HEK-293) GFP(u)-1 cell lines. Compared with controls, cells expressing either BRICHOS mutant protein consistently exhibited increased formation of insoluble aggregates, enhanced promotion of inositol-requiring enzyme 1-dependent splicing of X-box binding protein-1 (XBP-1), significant inhibition of proteasome activity, enhanced induction of mitochondrial cytochrome c release, and increased activations of caspase-4 and caspase-3, leading to apoptosis. These results suggest common cellular responses, including initiation of cell-death signaling pathways, to these lung disease-associated BRISPC proteins.