The Role And Mechanism Of RXRα Agonist Bexarotene In Improving The Structure And Function Of Heart In Angiotensin Ⅱ-induced Cardiac Hypertrophy Rats

Purpose:To observe the effect of RXRα agonistBexarotene(Bex)on the structure and function of heart in induced-angiotensinⅡ(AngⅡ)cardiac hypertrophy SpragueDawley(SD)rats.To investigate the possible regulatory role of Bex on cardiac structure and function in hypertrophic cardiomyopathy.Methods:A model of cardiac hypertrophy in Sprague-Dawley rats was established subcutaneous implantation ofosmotic pump(ALZET? 2006,DURECT)filled with AngⅡ.Thirty-two male SD rats were randomly divided into four groups with 8 animals in each:control group,Ang Ⅱ 200ng/kg/min group(AngⅡ),AngⅡ+Bex5 group(AngⅡ+Bex5)and AngⅡ+Bex10 group(AngⅡ+Bex10).The rat’s blood pressure was measured by tail-cuff method.The cardiac structural function was examined by color doppler ultrasound.The level of RXRα,ANP,Tom70 and Opa1 in cardiac tissue were measured by western blotting.The ultrastructure of mitochondria in cells was observed by transmission electron microscopy.The level of Ang Ⅱconcentrations were determined by radio immunoassay.Cardiomyocyte apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method(TUNEL).Results :(1)The level of serum Ang Ⅱin AngⅡ(307.83 ± 13.04 pg/ml),AngⅡ+Bex5(307.32 ± 12.74 pg/ml)and AngⅡ+Bex10 group(299.08 ± 12.00 pg/ml)were significantly higher than those in Control group(198.97±12.40 pg/m,lP﹤0.05).But the level of Ang in cardiac tissue was not significantly different(PⅡ ﹥0.05).(2)Compared with control group(SBP 114.51±9.34 mmHg,DBP 81.66±7.00mmHg),the systolic and diastolic blood pressure in AngⅡ(SBP 148.90±13.92 mmHg,DBP 95.35 ± 6.32mmHg),AngⅡ+Bex5(SBP 152.06 ± 21.70 mmHg,DBP 98.88 ±11.34mmHg)and AngⅡ+Bex10 group(SBP 149.54±15.93 mmHg,DBP 97.15±8.58mmHg)were significantly increased(P ﹤ 0.05).The heart mass index,left ventricular mass index,LVEDd,IVSd,LVPWd,and E/e’ in AngⅡ group were significantly higher than those in Control group(P < 0.05).Compared with AngⅡ group,the heart mass index,left ventricular mass index,IVSd and E/e’ in AngⅡ+Bex5 group and AngⅡ+Bex10 group were significantly Lower(P<0.05).(3)The myofilament and sarcomere in myocardial cells of the control group were arranged neatly,the mitochondria were normal.Sarcomere dissolution,mitochondrial morphological abnormalities,and fractured mitochondrial cristae could be seen in Ang Ⅱgroup.The myofilament and sarcomere in myocardial cells of the AngⅡ+ Bex5 and AngⅡ+Bex10 group were slightly irregular.Mitochondrial morphological structure was relatively normal and welling could be seen.(4)Compared with the control group,the level of ANP was significantly increased(P﹤0.05)in AngⅡ group.But compared with Ang Ⅱ group,the protein levels of ANP were significantly decreased(P﹤0.05)in in AngⅡ+Bex5 and AngⅡ+Bex10 group.Compared with the control group,the protein levels of RXRα,Tom70,Opa1 in cardiac tissue in AngⅡ,AngⅡ+Bex5 and AngⅡ+Bex10 group were significantly decreased(P<0.05).But compared with Ang Ⅱgroup,the protein levels of RXRα,Tom70,Opa1 in cardiac tissue in AngⅡ+ Bex5 and AngⅡ+Bex10 group were significantly increased(P<0.05).Conclusion:(1)RXRα agonist Bexarotene could improve the structure and function of heart in AngⅡ-induced cardiac hypertrophy rats;(2)Bexarotene significantly improvesmitochondrial ultrastructure of cardiomyocytes in AngⅡ-induced cardiac hypertrophy rats;(3)Bexarotene could inhibit the decreasedprotein levels of RXRα,Tom70 and Opa1 in AngⅡ-induced cardiac hypertrophy rats.