Background： Angiotensin II （Ang ll） 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 t...Background： Angiotensin II （Ang ll） 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 Jaggedl-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 y-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 11 group, treated with Ang I1; DAPT group, treated with DAPT; and Ang II ＋ DAPT group, treated with both Ang I1 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 fbr CD31, a vascular marker （P 〈 0.05 for both）. Meanwhile, Jaggedl protein was significantly increased, but gene expression for both Jagl and Heyl 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 Heyl 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 Heyl, a known Notch target, but did not affect the expression of Hey2, another Notch target gene. Conclusions： A Jaggedl-Heyl signal might mediate the impairment of angiogenesis induced by Ang II during cardiac hypertrophy.展开更多
文摘Background： Angiotensin II （Ang ll） 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 Jaggedl-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 y-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 11 group, treated with Ang I1; DAPT group, treated with DAPT; and Ang II ＋ DAPT group, treated with both Ang I1 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 fbr CD31, a vascular marker （P 〈 0.05 for both）. Meanwhile, Jaggedl protein was significantly increased, but gene expression for both Jagl and Heyl 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 Heyl 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 Heyl, a known Notch target, but did not affect the expression of Hey2, another Notch target gene. Conclusions： A Jaggedl-Heyl signal might mediate the impairment of angiogenesis induced by Ang II during cardiac hypertrophy.
