Aims: Angiotensin converting enzyme(ACE) 2 catalyses the cleavage of angiotensin(Ang) I to Ang 1- 9 and of Ang II to Ang 1- 7. ACE2 deficiency impairs cardiac contractility and upregulates hypoxia- induced genes, sugg...Aims: Angiotensin converting enzyme(ACE) 2 catalyses the cleavage of angiotensin(Ang) I to Ang 1- 9 and of Ang II to Ang 1- 7. ACE2 deficiency impairs cardiac contractility and upregulates hypoxia- induced genes, suggesting a link with myocardial ischaemia. We studied the expression of ACE2 after myocardial infarction(MI) in the rat as well as in human failing hearts. Methods and results: Rats were killed at days 1, 3, and 28 after MI, or treated for 4 weeks with the ACE inhibitor ramipril(1 mg/kg). Cardiac gene and protein expression of ACE and ACE2 were assessed by quantitative real- time reverse transcriptase polymerase chain reaction and immunohistochemistry/activity assays/in vitro autoradiography, respectively. Both ACE(P=0.022) and ACE2(P=0.015) mRNA increased in the border/ infarct area compared with the viable area at day 3 after MI. By day 28, increases in ACE(P=0.005) and ACE2(P=0.006) mRNA were also seen in the viable myocardium of MI rats compared with myocardium of control rats. ACE2 protein localized to macrophages, vascular endothelium, smooth muscle, and myocytes. Ramipril attenuated cardiac hypertrophy and inhibited cardiac ACE. In contrast, ramipril had no effect on cardiac ACE2 mRNA, which remained elevated in all areas of the MI rat heart. Immunoreactivfty of both ACE and ACE2 increased in failing human hearts. Conclusion: The increase in ACE2 after MI suggests that it plays an important role in the negative modulation of the renin angiotensin system in the generation and degradation of angiotensin peptides after cardiac injury.展开更多
Objective： To explore the efficacy of ursolic acid in sensitizing colon cancer cells to chemotherapy under hypoxia and its underlying mechanisms. Methods： Three colon cancer cell lines （RKO, LoVo, and SW480） were ...Objective： To explore the efficacy of ursolic acid in sensitizing colon cancer cells to chemotherapy under hypoxia and its underlying mechanisms. Methods： Three colon cancer cell lines （RKO, LoVo, and SW480） were used as in vitro models. 5-Fluorouracil （5-FU） and oxaliplatin were used as chemotherapeutic drugs. Cell viability and apoptosis were tested to evaluate the sensitivity of colon cancer cells to chemotherapy. The transcription and ex- pression levels of hypoxia-inducible factor-1α （HIF-1α）, multidrug resistance gene 1 （MDR1）, and vascular endothelial growth factors （VEGF） were assessed by quantitative real-time polymerase chain reaction （qRT-PCR） and im- munoblotting. Cycloheximide and MG132 were used to inhibit protein synthesis and degradation, respectively. In vitro tube formation assay was used to evaluate angiogenesis. Results： We demonstrated the chemosensitizing effects of ursolic acid with 5-FU and oxaliplatin in three colon cancer cell lines under hypoxia. This effect was correlated to its inhibition of MDR1 through HIF-la. Moreover, ursolic acid was capable of inhibiting HIF-1α accumulation with little effects on its constitutional expression in normoxia. In addition, ursolic acid also down-regulated VEGF and inhibited tumor angiogenesis. Conclusions： Ursolic acid exerted chemosensitizing effects in colon cancer cells under hypoxia by inhibiting HIF-la accumulation and the subsequent expression of the MDR1 and VEGF.展开更多
文摘Aims: Angiotensin converting enzyme(ACE) 2 catalyses the cleavage of angiotensin(Ang) I to Ang 1- 9 and of Ang II to Ang 1- 7. ACE2 deficiency impairs cardiac contractility and upregulates hypoxia- induced genes, suggesting a link with myocardial ischaemia. We studied the expression of ACE2 after myocardial infarction(MI) in the rat as well as in human failing hearts. Methods and results: Rats were killed at days 1, 3, and 28 after MI, or treated for 4 weeks with the ACE inhibitor ramipril(1 mg/kg). Cardiac gene and protein expression of ACE and ACE2 were assessed by quantitative real- time reverse transcriptase polymerase chain reaction and immunohistochemistry/activity assays/in vitro autoradiography, respectively. Both ACE(P=0.022) and ACE2(P=0.015) mRNA increased in the border/ infarct area compared with the viable area at day 3 after MI. By day 28, increases in ACE(P=0.005) and ACE2(P=0.006) mRNA were also seen in the viable myocardium of MI rats compared with myocardium of control rats. ACE2 protein localized to macrophages, vascular endothelium, smooth muscle, and myocytes. Ramipril attenuated cardiac hypertrophy and inhibited cardiac ACE. In contrast, ramipril had no effect on cardiac ACE2 mRNA, which remained elevated in all areas of the MI rat heart. Immunoreactivfty of both ACE and ACE2 increased in failing human hearts. Conclusion: The increase in ACE2 after MI suggests that it plays an important role in the negative modulation of the renin angiotensin system in the generation and degradation of angiotensin peptides after cardiac injury.
基金Project supported by the Zhejiang Science and Technology Research Program of China(No.2013C33229)the Traditional Chinese Medicine Program of Zhejiang Province of China(Nos.2013ZA081 and 2016ZA129)
文摘Objective： To explore the efficacy of ursolic acid in sensitizing colon cancer cells to chemotherapy under hypoxia and its underlying mechanisms. Methods： Three colon cancer cell lines （RKO, LoVo, and SW480） were used as in vitro models. 5-Fluorouracil （5-FU） and oxaliplatin were used as chemotherapeutic drugs. Cell viability and apoptosis were tested to evaluate the sensitivity of colon cancer cells to chemotherapy. The transcription and ex- pression levels of hypoxia-inducible factor-1α （HIF-1α）, multidrug resistance gene 1 （MDR1）, and vascular endothelial growth factors （VEGF） were assessed by quantitative real-time polymerase chain reaction （qRT-PCR） and im- munoblotting. Cycloheximide and MG132 were used to inhibit protein synthesis and degradation, respectively. In vitro tube formation assay was used to evaluate angiogenesis. Results： We demonstrated the chemosensitizing effects of ursolic acid with 5-FU and oxaliplatin in three colon cancer cell lines under hypoxia. This effect was correlated to its inhibition of MDR1 through HIF-la. Moreover, ursolic acid was capable of inhibiting HIF-1α accumulation with little effects on its constitutional expression in normoxia. In addition, ursolic acid also down-regulated VEGF and inhibited tumor angiogenesis. Conclusions： Ursolic acid exerted chemosensitizing effects in colon cancer cells under hypoxia by inhibiting HIF-la accumulation and the subsequent expression of the MDR1 and VEGF.
