title: 17-β Oestradiol prevents cardiovascular dysfunction in post-menopausal metabolic syndrome by affecting SIRT1/AMPK/H3 acetylation.
abstract: OBJECTIVE
  Oestrogen therapy is known to induce cardioprotection in post-menopausal metabolic syndrome (PMS). Hence, we investigated the effect of 17-β oestradiol (E2) on functional responses to angiotensin II and cardiovascular dysfunction in a rat model of PMS.
  
  
  METHODS
  PMS was induced in ovariectomized rats by feeding a high-fat diet for 10 weeks. Isometric tension responses of aortic rings to angiotensin II were recorded using an isometric force transducer. TUNEL assay and immunoblotting was performed to assess apoptosis and protein expression respectively in PMS.
  
  
  RESULTS
  Endothelial dysfunction in PMS was characterized by enhanced angiotensin II-induced contractile responses and impaired endothelial dependent vasodilatation. This was associated with an increased protein expression of AT1 receptors in the aorta and heart in PMS. PMS induced cardiac apoptosis by activating Bax and PARP protein expression. These changes were associated with a down-regulation in the expression of silent information regulation 2 homologue (SIRT1)/P-AMP-activated PK (AMPK) and increased H3 acetylation in aorta and heart. E2 partially suppressed angiotensin II-induced contractions, restored the protein expression of SIRT1/P-AMPK and suppressed H3 acetylation. The role of SIRT1/AMPK was further highlighted by administration of sirtinol and compound C (ex vivo), which enhanced angiotensin II contractile responses and ablated the protective effect of E2 on PMS.
  
  
  CONCLUSIONS
  Our results provide novel mechanisms for PMS-induced cardiovascular dysfunction involving SIRT1/AMPK/ histone H3 acetylation, which was prevented by E2. The study suggests that therapies targeting SIRT1/AMPK/epigenetic modifications may be beneficial in reducing the risk of cardiovascular disorders.
authors.affiliation: Laboratory of Chromatin Biology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India.
authors.forename: Dhaval Sharad
authors.initials: DS
authors.lastname: Bendale
authors.forename: Pinakin Arun
authors.initials: PA
authors.lastname: Karpe
authors.forename: Richa
authors.initials: R
authors.lastname: Chhabra
authors.forename: Sachin Prabhakarrao
authors.initials: SP
authors.lastname: Shete
authors.forename: Heta
authors.initials: H
authors.lastname: Shah
authors.forename: Kulbhushan
authors.initials: K
authors.lastname: Tikoo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017209:Apoptosis / Q000187:drug effects; D009202:Cardiomyopathies / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000008:administration & dosage*; D015914:Estrogen Replacement Therapy; D005260:Female; D006657:Histones / Q000378:metabolism*; D007333:Insulin Resistance; D024821:Metabolic Syndrome / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010052:Ovariectomy; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017698:Postmenopause / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D004791:Enzyme Inhibitors; D006657:Histones; D044140:Receptor, Angiotensin, Type 1; D051028:bcl-2-Associated X Protein; D004958:Estradiol; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D011065:Poly(ADP-ribose) Polymerases; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: AMPK; SIRT1; post-menopausal metabolic syndrome