title: Retinoid X receptor agonists inhibit hypertension-induced myocardial hypertrophy by modulating LKB1/AMPK/p70S6K signaling pathway.
abstract: BACKGROUND
  Retinoid X receptor (RXR) has been demonstrated to play an important role in cardiac development and has been implicated in cardiovascular diseases. This study aimed to examine the effects of RXRα agonist bexarotene on pathological left ventricular hypertrophy (LVH) in a spontaneously hypertensive rat (SHR) model and the underlying mechanism.
  
  
  METHODS
  WKY rats served as controls. SHRs were randomized into 3 groups at the age of 4 weeks and were treated (once daily for 12 weeks) with either bexarotene (30 or 100mg/kg body weight) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Neonatal cardiomyocytes were treated with AngII (10(-7) mmol/L) with or without the indicated concentration of RXRα ligand 9-cis-RA. The protein abundances of β-actin, RXRα, LKB1, phospho-LKB1, AMPK, phospho-AMPK, P70S6K, phospho-P70S6K, ACE, and AT1 receptor were measured along with blood pressure, body weight and angiotensin II (Ang II) levels. The effects of LKB1 downregulation by LKB1 small, interfering RNA were examined.
  
  
  RESULTS
  Treatment of SHRs with bexarotene resulted in significant inhibition of LVH without eliminating hypertension. Immunoblot with heart tissue homogenates from SHRs revealed that bexarotene activated the LKB1/AMPK signaling pathway and inhibited p70S6K. However, the increased Ang II levels in SHR serum and heart tissue were not reduced by bexarotene treatment. Treatment of cardiomyocytes with Ang II resulted in significantly reduced LKB1/AMPK activity and increased p70S6K activity. 9-cis-RA antagonized Ang II-induced LKB1/AMPK and p70S6K activation changes in vitro.
  
  
  CONCLUSIONS
  RXR agonists prevent the inhibition of the LKB1/AMPK/p70S6K pathway and regulate protein synthesis to reduce LVH. This antihypertrophic effect of bexarotene is independent of blood pressure.
authors.affiliation: First Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China;
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: First Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China;
authors.forename: Ruo-Bing
authors.initials: RB
authors.lastname: Ning
authors.affiliation: Echocardiological Department, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China;
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Lin
authors.affiliation: Cardiovascular Department, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China; caidajun@medmail.com.cn.
authors.forename: Da-Jun
authors.initials: DJ
authors.lastname: Chai
authors.affiliation: Cardiovascular Department, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China;
authors.forename: Chang-Sheng
authors.initials: CS
authors.lastname: Xu
authors.affiliation: Cardiovascular Department, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China;
authors.forename: Hong
authors.initials: H
authors.lastname: Xie
authors.affiliation: School of Pharmaceutical Sciences and Institute for Biomedical Research, Xiamen University, Xiamen, China.
authors.forename: Jin-Zhang
authors.initials: JZ
authors.lastname: Zeng
authors.affiliation: Cardiovascular Department, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China; caidajun@medmail.com.cn.
authors.forename: Jin-Xiu
authors.initials: JX
authors.lastname: Lin
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D000831:Animals, Newborn; D000077610:Bexarotene; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000209:etiology* / Q000517:prevention & control*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects*; D006973:Hypertension / Q000150:complications*; D032383:Myocytes, Cardiac / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D047488:Retinoid X Receptors / Q000819:agonists*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use
chemical_list: D034741:RNA, Small Interfering; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C488755:Stk11 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases
keywords: blood pressure; hypertension; hypertrophy; liver kinase B1; retinoid X receptor.