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

Abstract

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.

Loss of α(E)-catenin promotes Fas mediated apoptosis in tubular epithelial cells

“…There are three forms of α-catenin: neural (N), epithelial (E) and testis/heart (T) [8]. There is an increasing recognition that in addition to the well-established role in cell adhesion, α-catenin regulates multiple pathways controlling cell density, polarity, proliferation and apoptosis [9–11].…”

New functions for alpha-catenins in health and disease: from cancer to heart regeneration

“…Based on αT-catenin expression pattern, it is unclear how this largely cardiac-restricted α-catenin isoform might affect lung physiology. Interestingly, it was recently discovered that αT-catenin is expressed in lung within the cardiac sheath of pulmonary veins (Folmsbee et al, 2014). The same group found that αT-cat-null mice have altered lung mechanics demonstrated by increased pressure-volume curve area suggesting loss of αT-catenin affects lung hysteresis.…”

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

“…However, with age, these mice develop cardiomyopathy with decreased ejection fraction(7), consistent with the abundant expression of αT-cat in heart, and its recent link to familial arrythmogenic right ventricular cardiomyopathy(8). Our group has previously shown that αT-cat is present in the lungs, but in contrast to the more ubiquitously expressed αE-cat (found in lung epithelial, smooth muscle and endothelial cell types), αT-cat is restricted to the cardiomyocyte cell layer that surrounds pulmonary veins(9). Pulmonary veins have long been observed to become inflamed in murine models of asthma(10), but their role in regulating airway inflammation is largely not known, perhaps because the pulmonary veins develop separately from the sheath containing the arteries and airways of the lung(11).…”

“…Pulmonary veins have long been observed to become inflamed in murine models of asthma(10), but their role in regulating airway inflammation is largely not known, perhaps because the pulmonary veins develop separately from the sheath containing the arteries and airways of the lung(11). Despite their developmental independence, we have shown that subsets of airways can be found adjacent to the pulmonary veins in the mouse lung(9). …”