The Function Of Mg²⁺ And Solute Carrier Family 41 As Mg²⁺ Transporters In Monocrotaline Induced Pulmonary Arterial Hypertension

Mg²⁺ exchanger plays an important role in cardiovascular system, but the molecular mechanisms still largely remain unknown. By means of a particular mechanism of control of Mg²⁺ exchanger, mammalian cell regulates the absorption and release of Mg²⁺on cell membrane and storage of intracellular Mg²⁺, and it is in order that the concentration of magnesium strictly can be controlled within a narrow range?0.70-1.1mmol / L?.The solute carrier family 41?SLC41? encompasses three members SLC41A1,SLC41A2, and SLC41A3. Based on their distant homology to the bacterial Mg²⁺channel Mgt E, all have been linked to Mg²⁺transport. Among them, the SLC41A1 and SLC41A2 has been identified as Mg²⁺ transporters, however, the molecular biology and exact functions of SLC41A3 still largely remain unknown.The vascular pathological states in the pathogenesis of pulmonary arterial hypertension?PAH? owe much to an acute homeostasis imbalance of Ca²⁺in pulmonary aterial smooth muscle cells?PASMCs?. The present research results have shown that Ca²⁺ who determines the shrinkage, proliferation, migration and secretion of cell can be inhibited by Mg²⁺. In this present study, PAH rats were imitated by means of monocrotaline?MCT? intraperitoneal injection to mirror PAH characteristics,then we adjust the absorption of Mg²⁺levels in rats,observe the change of SLC41A1 and SLC41A2, SLC41A3 protein or m RNA in expression, as well as the change of serum magnesium concentration, to discuss the change of intracellular magnesium concentration in the mechanism of PAH pathogenesis, to study the pathogenesis of PAH and find more experimental basis for support for the breakthrough of treatment.Objective: To investigate the efforts and the pathologic physiology significance of Mg²⁺ and Solute Carrier family 41A1/2/3 as Mg²⁺ transporter in the pathogenic process of MCT-induced PAH, further examine the possibility pathogenesis of PAH, and find new experiment and theory foundations for PAH prevention and treatment.Methods:?1? Timecourse cruve of PASP and RVMI were examined in PAH rats induced by a single intraperitoneal injection of MCT at a dose of 50mg/kg.?2?On the basis of magnesium sulphate treatment by intragastric administration at 5m L/kg/d or10 m L/kg/d and intraperitoneal injection at 1m L/kg/d or 2m L/kg/d of 10% magnesium sulphate respectively in above PAH rats and normal SD rats, we also examined the timecourse cruve of body weight and survival rate.?3? Real-time Quantitative polymerase chain reaction?Real Time Q-PCR? and Western blot methods, measurement the expression levels of SLC41A1,SLC41A2,SLC41A3 protein or m RNA in rat PAs.Results: In comparison to the control rats,?1?PASP and RVMI began to increase in a week after MCT injection, and it had significant increase in 2 and 3w compared wih normal level. PAs wall thickening and stenosis, demonstrated that model rats exhibited profound PAH.?2?The survival rate and body weight of PAH rats were significantly decreased in 3w;?3?The expressions of SLC41A1,SLC41A2 m RNA and protein were dramaticlly increased in PAs of PH rats in 3w,however,the expressions of SLC41A3 m RNA and protein was dramaticlly decreased.With the magnesium supplement, in comparison to the PAH rats,?1?PASP and RVMI began to decrease in 3w after MCT injection. The effect of high dose intragastric administration group was more significant.?2?The survival rate and body weight of PAH rats were significantly increased in 3w; The effect of high dose intragastric administration group was more significant.?3?The expressions of SLC41A1,SLC41A2 m RNA were dramaticlly decreased in PAs of PH rats in 3w,however,the expressions of SLC41A3 m RNA was dramaticlly increased. The effect of high dose intragastric administration group was more significant.Conclusion: The expressions of SLC41A1,SLC41A2 m RNA and protein ware dramaticlly increased in PASMCs of PAH rats,SLC41A3 m RNA and protein was dramaticlly decreased.SLC41A1,SLC41A2 and SLC41A3 could adjust Mg²⁺concentration of the intracellular. It turned out that the SLC41A1,SLC41A2 and SLC41A3 may play an important role in the pathogenesis of PAH. Therefore, in the pathogenesis of PAH, proper adjustments for SLC41A1,SLC41A2 and SLC41A3 expression may in favor of maintaining the dynamic equilibrium of Mg²⁺ in PASMCs and regressing the progress of PAH. The results of present study offer a new research idea for the precaution and treatment of PAH.