Penumatsa KC, Toksoz D, Warburton RR, Hilmer AJ, Liu T, Khosla C, Comhair SA, Fanburg BL.Am J Physiol Lung Cell Mol Physiol. 2014 Oct 1;307(7):L576-85. doi: 10.1152/ajplung.00162.2014. Epub 2014 Aug 15.
Penumatsa KC, Fanburg BL.Am J Physiol Lung Cell Mol Physiol. 2014 Feb 15;306(4):L309-15. doi: 10.1152/ajplung.00321.2013. Epub 2013 Dec 27. Review.
I wanted to bring your attention to two recent papers in AJP Lung by Barry Fanburg’s group at Tufts University on tissue transglutaminase (TG2) in pulmonary hypertension (Penumatsa KC et al. AJPL Oct 1 2014 and Penumatsa and Fanburg BL AJPL Feb 14 2014). These very interesting papers highlight the role of TG2 in mediating and modulating the effects of hypoxia in the pulmonary vasculature in the context of PH. TG2 is a calcium-dependent enzyme that is expressed ubiquitously in multiple cell types including smooth muscle cells. TG2 is famous (or is it infamous?) for its role in celiac disease, but given its presence in other cell types, and its calcium dependency, there is much interest in its role in other diseases. TG2 is quite appealing in terms of both pathophysiology and a targetable mechanism given availability of blockers of this enzyme. (My personal interest in TG2 further lies in the fact that my uncle worked with Laszlo Lorand at Northwestern who was instrumental in our understanding of transglutaminases such as TG2 and factor XIII of the coagulation cascade).
The Fanburg group has previously found that TG2 is increased by hypoxia while conversely blocking TG2 prevents pulmonary hypertension in mouse models. The relevance to humans lies in increased serotonylated fibronectin (that results from increased TG2 activity) in patients with PH. In the Oct 1 paper, these authors explored the role of TG2 in mediating/modulating hypoxia effects on pulmonary artery smooth muscle cell proliferation (an aspect of vascular remodeling in PH that is in need of targeted therapies). Hypoxia was found to increase TG2 expression: an effect blocked by inhibition of HIF1a transcription factor. Separately, inhibition of the plasma membrane calcium sensing receptor blocked TG2 activity. The relevance of this latter mechanism lies in emerging evidence that the CaSR (also well known in other organ systems, particularly the parathyroid) is involved in vascular smooth muscle calcium regulation and cell proliferation. Furthermore, activators and inhibitors of CaSR are available (calcimimetics and calcilytics) and are probably being tested in the pulmonary artery. These types of studies (albeit in vitro) point to the complexity of interactions between calcium sensing/responsive pathways and proliferative/remodeling mechanisms in the pulmonary artery that likely contribute to the overall difficulty of alleviating structural and functional vascular changes in pulmonary hypertension. On the other hand, they are also exciting in terms of helping us understand how such interactions may play a role in other diseases that also involve both structural and functional changes at the level of smooth muscle (e.g. asthma).