| 김용숙¹, 권진숙¹, 홍문화¹, 조애신¹, 강완석¹, 안영근¹ ² , 정명호¹ ², 조정관¹ ², 박종춘¹ ², 강정채¹ ² |
Background: Cardiac fibrosis commonly occurs as the result of persistent healing response to chronic injuries in the heart after myocardial infarctions. 5-azacytidine (5AZ) is a widely used anti-tumor drug, and reported to block the pulmonary fibrosis. Here, the effect of 5AZ on cardiac fibrosis progression was studied in angiotensin II (Ang II)-induced cardiac injury model. Methods: Cardiac fibroblasts and cardiomyocytes were isolated from neonatal rats and stimulated with Ang II (0.1 μM) with or without 5AZ (10 μM) for 1 day or 5 days. For in vivo study, we divided animals into four groups; saline injection (Group 1), Ang II infusion (Group 2), Ang II infusion with 5AZ injection (Group 3), and 5AZ injection (Group 4). Cardiac fibrosis was induced by infusion of Ang II (65mg/kg/d) by an implantation of osmotic minipumps into mice for 14 days. Saline or 5AZ (1mg/kg, i.p) were injected every other day. Results: Connective tissue growth factor (CTGF), bcl2, collagen type I, and phosphorylated ERK were upregulated by Ang II whereas attenuated by 5AZ in fibroblasts. On the other hand in cardiomyocytes, phosphorylated Akt and bcl2 did not show responses to Ang II, whereas were upregulated by 5AZ. These data showed 5AZ inhibited the pro-proliferative signals induced by Ang II in cardiac fibroblasts rather than in cardiomyocytes. Cardiac fibrosis and the level of transforming growth factor (TGF)β-1, a strong inducer of fibrosis, were significantly reduced in Group 3 in compared with in Group 2. The increase of heart weight by Ang II in Group 2 was significantly reduced by 5AZ injection in Group 3. Blood pressure was also increased by Ang II (77.28±2.55mmHg in Group 1 vs. 90.21±15.13mmHg in Group 2, p<0.05), however it showed a trend to be lowered by 5AZ injection (79.25±9.79mmHg) without statistical significance, and it remained unchanged in Group 4 (72.18±12.01 mmHg). Conclusion: These data suggested that 5AZ could regulate the progression of cardiac fibrosis, and could be an additional benefit to cancer patients with cardiovascular risk factors.
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