title: Role of Jagged1-Hey1 Signal in Angiotensin II-induced Impairment of Myocardial Angiogenesis.
abstract: BACKGROUND
  Angiotensin II (Ang II) is a major contributor to the development of heart failure. However, the molecular and cellular mechanisms that underlie this process remain elusive. Inadequate angiogenesis in the myocardium leads to a transition from cardiac hypertrophy to dysfunction, and our previous study showed that Ang II significantly impaired the angiogenesis response. The current study was designed to examine the role of Jagged1-Notch signaling in the effect of Ang II during impaired angiogenesis and cardiac hypertrophy.
  
  
  METHODS
  Ang II was subcutaneously infused into 8-week-old male C57BL/6 mice at a dose of 200 ng·kg-1·min-1 for 2 weeks using Alzet micro-osmotic pumps. N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine tert-butyl ester (DAPT), a γ-secretase inhibitor, was injected subcutaneously during Ang II infusion at a dose of 10.0 mg·kg-1·d-1. Forty mice were divided into four groups (n = 10 per group): control group; Ang II group, treated with Ang II; DAPT group, treated with DAPT; and Ang II + DAPT group, treated with both Ang II and DAPT. At the end of experiments, myocardial (left ventricle [LV]) tissue from each experimental group was evaluated using immunohistochemistry, Western blotting, and real-time polymerase chain reaction. Data were analyzed using one-way analysis of variance test followed by the least significant difference method or independent samples t-test.
  
  
  RESULTS
  Ang II treatment significantly induced cardiac hypertrophy and impaired the angiogenesis response compared to controls, as shown by hematoxylin and eosin (HE) staining and immunohistochemistry for CD31, a vascular marker (P < 0.05 for both). Meanwhile, Jagged1 protein was significantly increased, but gene expression for both Jag1 and Hey1 was decreased in the LV following Ang II treatment, compared to that in controls (relative ratio for Jag1 gene: 0.45 ± 0.13 vs. 0.84 ± 0.15; relative ratio for Hey1 gene: 0.51 ± 0.08 vs. 0.91 ± 0.09; P < 0.05). All these cellular and molecular effects induced by Ang II in the hearts of mice were reduced by DAPT treatment. Interestingly, Ang II stimulated Hey1, a known Notch target, but did not affect the expression of Hey2, another Notch target gene.
  
  
  CONCLUSIONS
  A Jagged1-Hey1 signal might mediate the impairment of angiogenesis induced by Ang II during cardiac hypertrophy.
authors.affiliation: Department of Cardiology, Heart Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Ai-Li
authors.initials: AL
authors.lastname: Guan
authors.affiliation: Department of Cardiology, Heart Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Tao
authors.initials: T
authors.lastname: He
authors.affiliation: Department of Cardiology, Heart Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Yi-Bing
authors.initials: YB
authors.lastname: Shao
authors.affiliation: Department of Cardiology, Heart Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Chi
authors.affiliation: Department of Cardiology, Heart Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Dai
authors.affiliation: Department of Cardiology, Heart Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Heart Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Heart Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Heart Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Hua-Min
authors.initials: HM
authors.lastname: Ding
authors.affiliation: Department of Cardiology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266005, China.
authors.forename: Shang-Lang
authors.initials: SL
authors.lastname: Cai
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D000072100:Jagged-1 Protein / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018797:Cell Cycle Proteins; C120420:Hey1 protein, mouse; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein