| Background:Pulmonary arterial hypertension(PAH)is a progressive and malignant disease,whose main features are the remodeling of pulmonary small arteries and right ventricular,eventually leading to right ventricular failure and death.PAH lesions blocked blood vessels restricting blood flow through the pulmonary artery,increased right ventricular afterload and leaded to right ventricular hypertrophy and right ventricular dysfunction.Right ventricular function in patients is a major factor in determining the amount of symptoms,activity tolerance and survival time.Current treatment for the right heart is a hot research about PAH.Cardiac troponin I-interacting kinase(TNNI3K)is a cardiac-specific expression of a new kinase,and its expression level is higher in the left heart than that in the right.Many researchs suggested its involvement in the pathophysiology of ventricular remodeling.It has been reported that TNNI3 K as a key gene modificated heart failure and the gene expression of the stress-induced heart failure accelerated disease progression.And increased TNNI3 K kinase activity can induce the model of ventricular remodeling in mice and can accelerate the progression in left ventricular pressure overload mouse abdominal aortic coarctation model.But TNNI3 K and its inhibitors in right heart remodeling of PAH have not been reported.Objective:This study aims to build monocrotaline(MCT)-induced pulmonary artery hypertension model in rats.We researched that the role and molecular signaling pathways of TNNI3 K on right ventricular remodeling of PAH.To investigate the reversal effect of TNNI3 K inhibitors on right ventricular remodeling.Methods:To build PAH rat model,SD rats were given intraperitoneal injection of MCT,then were given TNNI3 K inhibitors fw01 interventions per day,for 21 days to stop feeding.The echocardiography,right heart catheterization and histopathology were used to identify their phenotype.Results:1.The identification of MCT-induced PAH and right heart remodeling in rats model:After MCT-induced PAH model SD rats three weeks,echocardiographic data show: right ventricular free wall thickness(RVWT),tricuspid annulus systolic displacement(TAPSE),pulmonary blood flow acceleration time / pulmonary ejection time were significantly worse than(PAT/PET)and normal control group(NC).The RVWT in MCT group(n = 17,1.185 ± 0.051cm)was 1.7 times of NC group(n = 8,0.702 ± 0.072cm)(P < 0.0001);The TAPSE in MCT rats(n = 17,2.212 ± 0.084cm)was less than NC group(n = 8,2.733 ± 0.220cm)by 81%(P < 0.05);The PAT / PET in MCT rats(n = 17,0.223 ± 0.016)was less than NC group(n = 8,0.398 ± 0.016)by 56%(P < 0.0001).Right heart catheterization data show that rat rats mean pulmonary artery pressure(mPAP),right ventricular systolic pressure(RVSP)and right ventricular hypertrophy index(RV/LV+S)were gradually increased.The mPAP in MCT group(n = 4,34.08 ± 1.64mmHg)was 1.5 times of NC group(n = 7,22.37 ± 1.11 mm Hg)(P < 0.001),the RVSP in MCT rats(n = 5,48.15 ± 2.35mmHg)was 2.1 times of NC group(n = 7,22.99 ± 1.02mmHg)(P < 0.0001).The RV / LV + S in the MCT group(n = 2,0.374 ± 0.040)was 1.9 times of NC group rats(n = 7,0.202 ± 0.015)(P < 0.01).2.The identification of the prevention or reversal of phenotype to TNNI3 K inhibitor on MCT-induced PAH in rats :The different concentrations drug of TNNI3 K specific inhibitor fw01 were given on MCT-induced PAH in rats.The echocardiography indicators RVWT,TAPSE,PAT / PET significantly improved.The RVWT in MCT + high dose group(n = 12,0.933 ± 0.077cm)was less than MCT group(n = 17,1.185 ± 0.514cm)by 79%(P < 0.05);MCT + middle dose group(n = 18,0.930 ± 0.045 cm)was less than MCT group by 78%(P < 0.01);MCT + low dose group(n = 11,0.827 ± 0.035cm)was less than MCT group by 70%(P < 0.0001).The TAPSE in MCT + high dose group(n = 12,2.535 ± 0.170cm)and MCT group(n = 17,2.212 ± 0.084cm)had no significant difference(P > 0.05);MCT + middle dose group(n = 18,2.652 ± 0.182cm)was 1.2 times of MCT group(P < 0.05);MCT + low dose group(n = 11,2.977 ± 0.088cm)was 1.4 times of MCT group(P < 0.0001).The PAT/PET in MCT + high dose group(n = 12,0.330 ± 0.028)was 1.5 times of MCT group(n = 17,0.223 ± 0.016)(P < 0.05);MCT + middle dose group(n = 18,0.345 ± 0.022)was 1.6 times of MCT group(P < 0.0001);MCT + low dose group(n = 11,0.318 ± 0.040)was 1.4 times of MCT group(P < 0.05).After the intervention of TNNI3 K specific inhibitor fw01,the mPAP in MCT + middle dose group(n = 5,25.81 ± 1.38mmHg)was significant lower than that in MCT group(n = 4,34.08 ± 1.64 mm Hg)(P < 0.05).There was no difference between MCT + middle dose group(n = 4,39.97 ± 3.92mmHg)and MCT group(n = 5,48.15 ± 2.35mmHg)(P > 0.05),but decreased.No difference(P > 0.05)of RV/LV+S between MCT + middle dose group(n = 4,0.386 ± 0.040)and MCT group(n = 2,0.374 ± 0.040).Pathological tissue and staining were used to evaluate the changes of right heart structure and cardiomyocytes in each group.The right ventricular of NC groupwall is thin and its myocardial cells arranged neatly,with a small amount of fibrous tissue.The right ventricular wall of the MCT group was thickened,the hypertrophy and hypertrophy of the myocardium were significantly increased in the MCT group.The right ventricular wall was thickened,the hypertrophy and hypertrophy of the myocardium were significantly increased in the MCT group.Compared to MCT group,the right ventricular wall of the rat was thinner,the volume of myocardial cells was smaller,and the fibrosis of the myocardium was not significant.The relative thickness of right ventricular wall and the relative area of cardiomyocytes were measured by image analysis software.The results showed that the relative thickness of right ventricular wall in MCT group(n = 3,134.4 ± 4.93)was 1.2 times of NC group(n = 3,115.9 ± 2.19)(P < 0.01).The rats in the MCT + middle dose group(n = 3,118.3 ± 5.30)was less than MCT group by 12%(P < 0.05).Compared with the right thickness in the MCT group,the relative area of cardiomyocytes showed that MCT group(n = 3,3493 ± 161.90)was 1.7 times of NC group(n = 3,2075 ± 65.33)(P < 0.0001).The relative area of myocardial cells(2621 ± 148.20)in MCT + middle dose group treated with inhibitor fw01(n = 3)was less than MCT group by 75%(P < 0.01).Conclusions:1.Rats induced by MCT for three weeks can be successfully constructed model of PAH;2.TNNI3 K promoted the remodeling of right heart in rats with PAH,which was a target for intervention on the remodeling of right heart;3.TNNI3 K specific inhibitors can prevent or ameliorate the remodeling of right heart in PAH,with a clinical conversion value. |
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