Retinoid X Receptor Agonists Inhibit Hypertension-induced Myocardial Hypertrophy And The Underlying Mechanism

Objective:To explore the effects of Retinoid X receptor (RXR)agonistsonpathological left ventricular hypertrophy (LVH) and Angiotensin II (AngII)level in the blood and Heart Tissueof spontaneous hypertension rat(SHR),andinvestigatethe regulating effect of RXRaagonists onLKB1/AMPK/mTOR/p70S6Ksignaling pathway.Methods：Usespontaneously hypertensive rat (SHR) as animal model of hypertensionand cardiac hypertrophy. SHRs were randomized into three groups (six rats/group) atthe age of4weeks and were treated with theRXRαsynthetic agonistbexarotene (at thedoses of30or100mg/kg body weight (mpk), or placebo alone for12weeks.UseWistar Kyoto(WKY) rats as control. Noninvasive bloodpressuremeasurements weremade withBP98A tail cuff system.Transthoracic echocardiography was performed tomeasure end-diastolic LV internaldiameter (LVIDd), posterior wall thickness(LVPWd), andinterventricularseptal thickness (IVSd),ejection fractions (EF).Bodyweight(BW),heart weight and ventricle weight were monitored. Angiotensin II (AngII) concentrations were determined by radio immunoassay.Cardiomyocytes weretreated for24h withAngIIwith or without the RXRαnatural ligandagonist9-cis-retinoic acid. PhosphorylatedLKB1(P-LKB1), phosphorylatedP70S6K(P-P70S6K) and RXRαlevel were measuredwith westernblot.Results:1.Compared with WKYrats, blood pressureof SHRs was significantlyincreased (191.8±6.24mmHg vs120.5±9.96mmHg) and not reduced by Bexarotenetreatment (30mg/kg/d:185.6±7.27mmHg,100mg/kg/d:184.7±7.35).2. The leftventricular weight, left ventricular mass index (left ventricular weight/body weight),ventricular thicknessof SHRs were significantly elevated compared to these of WKYrats.These chances were remarkably inhibited by Bexarotene treatment.3. Bexarotenetreatment increased RXR expressionin SHRs, but not affect Ang II level in bloodserum and heart tissue.4. The cardiacLKB1activitie was remarkablydecreased while the p70S6Kactivitie was increased in SHRs, and these changes were antagonized byBexarotenetreatment.5.9-cis-RA antagonizes the effect of Ang IIon LKB1andp70S6K activation and Ang II treatment not influence the expression of RXRαin ratcardiac myocytes.Conclusion: RXR agonists can prevent left ventricular hypertrophy in SHR byregulation of LKB1-p70S6K signal pathway.This antihypertrophic effectofRXRαagonists is independent of blood pressure and Ang II.