Cardiomyocytes of the Heart and Pulmonary Veins: Novel Contributors to Asthma?

Recent genome-wide association studies have implicated both cardiac and pulmonary vein-related genes in the pathogenesis of asthma. Since cardiac cells are not present in lung airways or viewed to affect the immune system, interpretation of these findings in the context of more well-established contributors to asthma has remained challenging. However, cardiomyocytes are present in the lung, specifically along pulmonary veins, and recent murine models suggest that cardiac cells lining the pulmonary veins may contribute to allergic airway disease. Notably, the cardiac cell-junction protein αT-catenin (αT-cat, CTNNA3), which is implicated in occupational and steroid-resistant asthma by clinical genetic data, appears to play an important role in regulating inflammation around the cardiac cells of pulmonary veins. Beyond the potential contribution of pulmonary veins, clinical data directly examining cardiac function through echocardiography have found strong associations between asthmatic phenotypes and the mechanical properties of the heart. Together, these data suggest that targeting the function of cardiac cells in the pulmonary veins and/or heart may allow for novel and potentially efficacious therapies for asthma, particularly in challenging cases of steroid-resistant asthma.

The cardiomyocyte protein αT-catenin contributes to asthma through regulating pulmonary vein inflammation.

BACKGROUND: Recent genome-wide association studies have identified single nucleotide polymorphisms in the gene encoding the protein αT-catenin (CTNNA3) that correlate with both steroid-resistant atopic asthma and asthmatic exacerbations. α-Catenins are important mediators of cell-cell adhesion, and αT-catenin is predominantly expressed in cardiomyocytes. In the lung αT-catenin appears to be exclusively expressed in cardiomyocytes surrounding the pulmonary veins (PVs), but its contribution to atopic asthma remains unknown. OBJECTIVE: We sought to understand the role of αT-catenin in asthma pathogenesis. METHODS: We used αT-catenin knockout mice and a house dust mite (HDM) extract model of atopic asthma, with assessment by means of forced oscillation, bronchoalveolar lavage, and histologic analysis. RESULTS: We found that the genetic loss of αT-catenin in mice largely attenuated HDM-induced airway inflammation and airway hyperresponsiveness to methacholine. Mice lacking αT-catenin that were exposed to HDM extract had reduced PV inflammation, specifically near the large veins surrounded by cardiac cells. The proximity of the airways to PVs correlated with the severity of airway goblet cell metaplasia, suggesting that PVs can influence the inflammatory milieu of adjacent airways. Loss of αT-catenin led to compensatory upregulation of αE-catenin, which itself has a defined anti-inflammatory function. CONCLUSION: These data mechanistically support previous clinical and genetic associations between αT-catenin and the development of atopic asthma and suggest that PVs might have an underappreciated role in allergic airway inflammation.

The cardiac protein αT-catenin contributes to chemical-induced asthma.

Ten to 25% of adult asthma is occupational induced, a subtype caused by exposure to workplace chemicals. A recent genomewide association study identified single-nucleotide polymorphisms in the cardiac protein αT-catenin (αT-cat) that correlated with the incidence and severity of toluene diisocyanate (TDI) occupational asthma. αT-cat is a critical mediator of cell-cell adhesion and is predominantly expressed in cardiomyocytes, but its connection to asthma remains unknown. Therefore, we sought to determine the primary αT-cat-expressing cell type in the lung and its contribution to lung physiology in a murine model of TDI asthma. We show that αT-cat is expressed in lung within the cardiac sheath of pulmonary veins. Mechanically ventilated αT-cat knockout (KO) mice exhibit a significantly increased pressure-volume curve area compared with wild-type (WT) mice, suggesting that αT-cat loss affects lung hysteresis. Using a murine model of TDI asthma, we find that αT-cat KO mice show increased airway hyperresponsiveness to methacholine compared with WT mice. Bronchoalveolar lavage reveals only a mild macrophage-dominant inflammation that is not significantly different between WT and KO mice. These data suggest that αT-cat may contribute to asthma through a mechanism independent of inflammation and related to heart and pulmonary vein dysfunction.

αT-catenin in restricted brain cell types and its potential connection to autism.

BACKGROUND: Recent genetic association studies have linked the cadherin-based adherens junction protein alpha-T-catenin (αT-cat, CTNNA3) with the development of autism. Where αT-cat is expressed in the brain, and how its loss could contribute to this disorder, are entirely unknown. METHODS: We used the αT-cat knockout mouse to examine the localization of αT-cat in the brain, and we used histology and immunofluorescence analysis to examine the neurobiological consequences of its loss. RESULTS: We found that αT-cat comprises the ependymal cell junctions of the ventricles of the brain, and its loss led to compensatory upregulation of αE-cat expression. Notably, αT-cat was not detected within the choroid plexus, which relies on cell junction components common to typical epithelial cells. While αT-cat was not detected in neurons of the cerebral cortex, it was abundantly detected within neuronal structures of the molecular layer of the cerebellum. Although αT-cat loss led to no overt differences in cerebral or cerebellar structure, RNA-sequencing analysis from wild type versus knockout cerebella identified a number of disease-relevant signaling pathways associated with αT-cat loss, such as GABA-A receptor activation. CONCLUSIONS: These findings raise the possibility that the genetic associations between αT-cat and autism may be due to ependymal and cerebellar defects, and highlight the potential importance of a seemingly redundant adherens junction component to a neurological disorder.

Ewing sarcoma EWS protein regulates midzone formation by recruiting Aurora B kinase to the midzone.

Ewing sarcoma is a malignant bone cancer that primarily occurs in children and adolescents. Eighty-five percent of Ewing sarcoma is characterized by the presence of the aberrant chimeric EWS/FLI1 fusion gene. Previously, we demonstrated that an interaction between EWS/FLI1 and wild-type EWS led to the inhibition of EWS activity and mitotic dysfunction. Although defective mitosis is considered to be a critical step in cancer initiation, it is unknown how interference with EWS contributes to Ewing sarcoma formation. Here, we demonstrate that EWS/FLI1- and EWS-knockdown cells display a high incidence of defects in the midzone, a midline structure located between segregating chromatids during anaphase. Defects in the midzone can lead to the failure of cytokinesis and can result in the induction of aneuploidy. The similarity among the phenotypes of EWS/FLI1- and EWS siRNA-transfected HeLa cells points to the inhibition of EWS as the key mechanism for the induction of midzone defects. Supporting this observation, the ectopic expression of EWS rescues the high incidence of midzone defects observed in Ewing sarcoma A673 cells. We discovered that EWS interacts with Aurora B kinase, and that EWS is also required for recruiting Aurora B to the midzone. A domain analysis revealed that the R565 in the RGG3 domain of EWS is essential for both Aurora B interaction and the recruitment of Aurora B to the midzone. Here, we propose that the impairment of EWS-dependent midzone formation via the recruitment of Aurora B is a potential mechanism of Ewing sarcoma development.