title: Hydrochlorothiazide modulates ischemic heart failure-induced cardiac remodeling via inhibiting angiotensin II type 1 receptor pathway in rats.
abstract: OBJECTIVE
  Our previous study indicates that hydrochlorothiazide inhibits transforming growth factor (TGF)-β/Smad signaling pathway, improves cardiac function and reduces fibrosis. We determined whether these effects were common among the diuretics and whether angiotensin II receptor type 1 (AT1) signaling pathway played a role in these effects.
  
  
  METHODS
  Heart failure was produced by ligating the left anterior descending coronary artery in adult male Sprague Dawley rats. Two weeks after the ligation, 70 rats were randomly divided into five groups: sham-operated group, control group, valsartan group (80 mg/kg/d), hydrochlorothiazide group (12.5 mg/kg/d) and furosemide group (20 mg/kg/d). In addition, neonatal rat ventricular fibroblasts were treated with angiotensin II.
  
  
  RESULTS
  After eight-week drug treatment, hydrochlorothiazide group and valsartan group but not furosemide group had improved cardiac function (ejection fraction was 49.4±2.1%, 49.5±1.8% and 39.9±1.9%, respectively, compared with 40.1±2.2% in control group), reduced cardiac interstitial fibrosis and collagen volume fraction (9.7±1.2%, 10.0±1.3% and 14.1±0.8%, respectively, compared with 15.9±1.1% in control group), and decreased expression of AT1, TGF-β and Smad2 in the cardiac tissues. In addition, hydrochlorothiazide reduced plasma angiotensin II and aldosterone levels. Furthermore, hydrochlorothiazide inhibited angiotensin II-induced TGF-β1 and Smad2 protein expression in the neonatal rat ventricular fibroblasts.
  
  
  CONCLUSIONS
  Our study indicates that the cardiac function and remodeling improvement after ischemic heart failure may not be common among the diuretics. Hydrochlorothiazide may reduce the left ventricular wall stress and angiotensin II signaling pathway to provide these beneficial effects.
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Zhong-Shan University, Guangzhou, China.|Department of Geriatrics, Huizhou Municipal Central Hospital, Guangdong, China.
authors.forename: Jinghong
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Zhong-Shan University, Guangzhou, China.
authors.forename: Xuanlan
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Zhong-Shan University, Guangzhou, China.
authors.forename: Chufan
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Zhong-Shan University, Guangzhou, China.
authors.forename: Guihua
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Zhong-Shan University, Guangzhou, China.
authors.forename: Longyun
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Zhong-Shan University, Guangzhou, China.
authors.forename: Xiuren
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005665:Furosemide / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D008297:Male; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D020127:Recovery of Function; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000068756:Valsartan / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D004232:Diuretics; D044140:Receptor, Angiotensin, Type 1; D051899:Smad2 Protein; C497784:Smad2 protein, rat; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D006852:Hydrochlorothiazide; D000804:Angiotensin II; D000450:Aldosterone; D005665:Furosemide; D000068756:Valsartan
keywords: Cardiac remodeling; Congestive heart failure; Hydrochlorothiazide; Renin-Angiotensin-Aldosterone system; TGF-β