The Effect Of MTMR14 Deletion On Airway Hyper Reactivity In Asthma Mice And Its Mechanism

MTMR14 is a novel phosphoinositide phosphatase that is highly expressed in testis,skeletal muscle and myocardium.Its loss leads to intracellular calcium disorders,causing numerous muscle diseases such as central nuclear myopathy,skeletal muscle aging,muscle weakness and muscle fatigue.In addition,the gene regulates cell proliferation,migration,and atherogenesis.Asthma is a heterogeneous disease Which is by airway hyperresponsiveness and chronic airway inflammation,usually caused by chronic inflammation of the bronchi and microtraches,and airway obstruction.In skeletal muscle,we have reported that the absence of MTMR14 can lead to intracellular calcium disorders that affect the normal function of skeletal muscle.Recently,we found that MTMR14 is also highly expressed in airway smooth muscle,so we speculate that the loss of MTMR14 may affect the contraction of tracheal smooth muscle and the formation of asthma.To test this hypothesis,we first examined the expression of MTMR14 in normal and asthmatic mice.We found that MTMR14 expression is down-regulated in asthmatic mice,suggesting that MTMR14 may play a role in asthma formation.We then used wild-type and MTMR14 knockout mice to establish an asthma model to study the effect of MTMR14 deletion on airway hyperresponsiveness in asthmatic mice and its mechanism.The results were as follows: airway inflammatory cell infiltration,airway wall remodeling,airway hyperresponsiveness,and airway resistance were significantly enhanced in MTMR14 knockout asthma mice;further studies found that deletion of MTMR14 resulted in Th2 cytokine IL-4,the expression of IL-13 was up-regulated,and the expression of mucin Muc5 ac,TNF,and NOX4 was also significantly up-regulated,which was consistent with the previous phenotype findings.In addition,we found that the absence of MTMR14 resulted in an increase in intracellular calcium in the smooth muscle of the trachea,and an abnormal L-type calcium channel current,which may be related to the down-regulation of Cav1.2 in the L-type calcium channel family due to the loss of MTMR14.In addition,we screened a small molecule compound,Benidipine HCl,that can be used to relax the contraction of isolated tracheal rings in mice induced by high potassium and ACh.Benidipine HCl is a long-acting second-generation dihydropyridine calcium antagonist that is now clinically used as an antihypertensive and anti-angina drug.Our study found that Benidipine HCl can inhibit the contraction of isolated tracheal rings induced by high potassium and ACh in mice by blocking L-type calcium channels and NSCCs to inhibit extra-calcium influx and intra-calcium release.Taken together,our results indicate that deletion of MTMR14 affects L-type calcium channel currents in airway smooth muscle cells by affecting intracellular calcium levels in tracheal smooth muscle cells and leads to airway hyperresponsiveness;Benidipine HCl can regulate intracellular calcium leves by blocking L-type calcium channels and NSCCs and inhibit tracheal smooth muscle contraction,which may be used to treat tracheal spasm.