Hydrogen Sulfide Alleviates Myocardial Fibrosis In Rats With Uremia Through The Inhibition Of Apoptosis By Regulating JAK2/STAT3 Signaling Pathway

Objective:Uremic cardiomyopathy is a cardiomyopathy secondary to renal failure.In recent years,with the prolongation of life of the patients with uremia,the myocardial damage caused by uremia is increasingly prominent,cardiovascular disease has become the primary cause of death in patients with uremia,and myocardial fibrosis is one of the important pathological changes of uremic cardiomyopathy.Hydrogen sulfide has the protective effects of anti-inflammatory,antioxidation,anti apoptosis and so on,and its protective effect on cardiovascular system has been proved by many studies.In this study,a rat model of uremia was established,and sodium hydrosulfide,as H₂S donor,was used to treat rats with uremia.The study aims to observe the effect of H₂S on myocardial fibrosis in rats with uremia and to explore its potential mechanisms.Methods:Forty male Sprague-Dawley rats were randomly divided into4 groups:Sham operation group?Sham group?,uremia model group?UCM group?,uremia rats treated with H₂S group?UCM+H₂S group?,sham operation rats treated with H₂S group?H₂S group?.Rats in Sham group and H₂S group undergo the surgery of freeing bilateral kidney,and rats in UCM group and UCM+H₂S group undergo 5/6 nephrectomy.After one week of recuperation,rats in UCM+H₂S group and H₂S group were given a daily intraperitoneal injection of NaHS at a dose of 50?mol/kg.Rats in Sham group and UCM group were given normal saline with an equal volume.8 weeks after the intervention,24 hours urine samples of rats were collected to detect the excretion of urine protein,body weight?BW?of rats were measured,echocardiography was performed to detect cardiac function of rats after anesthesia,serum urea nitrogen?BUN?and creatinine?Cr?were detected before rats were killed,and then the hearts were harvested and the hearts weight?HW?were measured to calculate the ratios of heart weight to body weight?HW/BW?.Concentration of hydrogen sulfide in rat myocardial tissue was detected by Elisa methods.Masson staining was used to observe collagen deposition in the myocardium.The Tunel staining was used to observe the apoptosis of cardiac myocytes.Western Blotting was used to detect the expression of fibrosis related proteins and apoptosis related proteins in myocardium.Results:1.The result of urine protein quantitation indicated that,the excretion of urine protein in UCM group and UCM+H₂S group were significantly higher than that in Sham group?p?0.05?;and compared with the UCM group,the excretion of urine protein was slightly decreased in UCM+H₂S group?p>0.05?.2.The results of BUN and Cr level revealed that,the level of BUN and Cr in UCM group and UCM+H₂S group were significantly higher than that in Sham group?p?0.05?;compared with UCM group,the level of BUN and Cr were decreased significantly in UCM+H₂S group?p?0.05?.3.The result of hydrogen sulfide concentration in rat myocardial tissue revealed that,the concentration of hydrogen sulfide in myocardial tissue of UCM group was significantly higher than that of Sham group?p?0.05?;and compared with UCM group,hydrogen sulfide concentration was significantly lower in myocardial tissue of UCM+H₂S group.4.The result of echocardiography indicated that,compared with the Sham group,the thickness of the interventricular septum increased significantly and the EF value decreased significantly in UCM group?p?0.05?;and compared with UCM group,the thickness of interventricular septum was significantly decreased?p?0.05?,and the EF value was increased,but the difference was not statistically significant?P>0.05?in UCM+H₂S group.5.There were no significant difference in body weight and heart weight in each group?P>0.05?;compared with Sham group,the BW/HW was significantly increased in UCM group?p?0.05?;compared with UCM group,the BW/HW was decreased significantly in UCM+H₂S group?p?0.05?.6.The result of Masson staining showed that,the collagen deposition was more obvious in UCM group than that in Sham group;the collagen deposition was significantly relieved in UCM+H₂S group than that in UCM group.7.The expression levels of fibrosis related protein revealed that,the expression levels of MMP2,MMP9,MMP17 were significantly increased and the expression of TIMP1 was significantly decreased in UCM group compare with Sham group?p?0.05?;compared with UCM group,the expression levels of MMP2,MMP9,MMP17 were significantly decreased and the expression of TIMP1 was significantly increased in UCM+H₂S group?p?0.05?.8.The result of Tunel staining showed that,the number of Tunel-positive cardiomyocytes in UCM group was significantly higher than that in Sham group,and compared with UCM group,the number of Tunel-positive cardiomyocytes was significantly decreased.9.The expression levels of apoptosis related protein revealed that,compared with Sham group,the expression levels of Caspase3,Caspase6,Bax were significantly increased in UCM group?p?0.05?;and the expression levels of Caspase3,Caspase6,Bax were significantly decreased in UCM+H₂S group?p?0.05?.10.The expression levels of JAK2/STAT3 revealed that,compared with Sham group,the expression levels of JAK2 and STAT3 were significantly increased in UCM group?p?0.05?;compared with UCM group,the expression levels of JAK2 and STAT3 were significantly decreased in UCM+H₂S group?p?0.05?.Conclusion:H₂S can alleviate myocardial fibrosis in rats with uremia,and the mechanism may involve the inhibition of apoptosis by regulating the JAK2/STAT3 signaling pathway.