title: Olmesartan attenuates cardiac remodeling through DLL4/Notch1 pathway activation in pressure overload mice.
abstract: BACKGROUND
  Notch1 signaling controls the cardiac adaptation to stress. We therefore aimed to validate whether olmesartan, a widely used angiotensin II type 1 receptor blocker, ameliorates cardiac remodeling and dysfunction via delta-like ligand 4 (DLL4)/Notch1 pathway in mice with chronic pressure overload.
  
  
  METHODS
  Cardiac pressure overload was produced by transverse aortic constriction (TAC). A total of 35 wide-type C57BL/6J mice were randomly divided into sham group, TAC group, TAC + olmesartan group, and TAC + olmsartan + DAPT group (DAPT: γ-secretase inhibitor, Notch signaling inhibitor). Saline (10 mL·kg(-1)·d(-1)) or the same volume of olmesartan liquor (3 mg·kg(-1) d(-1)) was administered by gavage, and DAPT (10 μmole·kg(-1)·d(-1)) by peritoneal injection. After 28 days of treatment, cardiac hemodynamics, echocardiography, and histology were evaluated, followed by quantitative polymerase chain reaction of fetal gene (ANP and SAA) expression. Notch1-related proteins and ERK1/2 were examined by western blot, and the serum level of angiotensin II was determined by means of enzyme-linked immunosorbent assay kits.
  
  
  RESULTS
  Persistent pressure overload-induced left ventricular hypertrophy, dysfunction, fibrosis, and microcirculation dysfunction, together with the upregulation of angiotensin II, ERK1/2, and fetal gene expression. By the activation of DLL4/Notch1, olmesartan decreased left ventricular hypertrophy and fibrosis, preserved cardiac function, and improved capillary density and coronary perfusion. All these curative effects were suppressed by pharmacological blockade of Notch signaling with DAPT.
  
  
  CONCLUSIONS
  Our findings identify a heretofore unknown pharmacological mechanism that olmesartan improves cardiac remodeling and function via DLL4/Notch1 pathway activation in mice with chronic pressure overload, which may present a new therapeutic target for hypertension.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Jieyun
authors.initials: J
authors.lastname: You
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Guoliang
authors.initials: G
authors.lastname: Jiang
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000804:Angiotensin II / Q000235:genetics; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D002135:Calcium-Binding Proteins; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D005355:Fibrosis; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics; D051881:Receptor, Notch1 / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047228:Angiotensin II Type 1 Receptor Blockers; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D004151:Dipeptides; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D013777:Tetrazoles; D000804:Angiotensin II; C437965:olmesartan; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3