Transgelin-2 as a therapeutic target for asthmatic pulmonary resistance

Abstract

There is a clinical need for new bronchodilator drugs in asthma, because more than half of asthmatic patients do not receive adequate control with current available treatments. We report that inhibition of metallothionein-2 protein expression in lung tissues causes the increase of pulmonary resistance. Conversely, metallothionein-2 protein is more effective than β-agonists in reducing pulmonary resistance in rodent asthma models, alleviating tension in tracheal spirals, and relaxing airway smooth muscle cells (ASMCs). Metallothionein-2 relaxes ASMCs via transgelin-2 (TG2) and induces dephosphorylation of myosin phosphatase target subunit 1 (MYPT1). We identify TSG12 as a nontoxic, specific TG2-agonist that relaxes ASMCs and reduces asthmatic pulmonary resistance. In vivo, TSG12 reduces pulmonary resistance in both ovalbumin- and house dust mite-induced asthma in mice. TSG12 induces RhoA phosphorylation, thereby inactivating the RhoA-ROCK-MYPT1-MLC pathway and causing ASMCs relaxation. TSG12 is more effective than β-agonists in relaxing human ASMCs and pulmonary resistance with potential clinical advantages. These results suggest that TSG12 could be a promising therapeutic approach for treating asthma.

Transgelin-2 in immunity: Its implication in cell therapy

“…The deleterious impact of transgelin‐2‐overexpressing cytotoxic T cells is not expected because of its endogenous nature in T cells, which has not been reported thus far. Notably, transgelin‐2 has been suggested as a promising antasthmatic drug target in a recent study; its agonist, TSG12, relaxes both human and mice airway smooth muscle cells and reduces pulmonary resistance without detectable toxicity or desensitization . Taken together, transgelin‐2‐mediated actin and LFA‐1‐ICAM‐1 axis concurrent enhancement may be a safe and potential supplementary regime for conventional cell‐mediated cancer immunotherapies.…”

Intercellular communication controls agonist-induced calcium oscillations independently of gap junctions in smooth muscle cells

“…The vessel/airway wall undergoes significant pathological changes in the smooth muscle 1 and in the extracellular matrix (ECM) that surrounds and supports the cells 2,3 with the onset of disease. The search for mechanisms that underlie the development of these diseases and the search for novel therapies has largely focused on the smooth muscle cells (SMCs) 4,5 , as they are the primary effectors of constriction. The pathological changes in the ECM 2,6 , on the other hand, have not received much attention.…”

Beyond T2-inflammation: What Does the Future Hold for Severe Asthma?

“…Whether this represents a potential therapeutic target requires further study. Animal studies have demonstrated that Metallothionein-2 (MT-2) can relax ASM and reduce pulmonary resistance via transgelin-2 (TG2) 49 . In vitro, treatment of human ASM cells with the specific TG2 agonist, TSG12, reduced resistance more effectively than β 2 -agonists and may represent a further target for smooth muscle dysfunction in asthma.…”