Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Circ J. 2010 Jan;74(1):109-19. doi: 10.1253/circj.cj-09-0486. Epub 2009 Dec 7.
Although therapeutic angiogenesis is a most promising strategy for the treatment of myocardial infarction (MI), it remains unknown if and how endogenous angiogenesis inhibitors, such as endostatin, regulate angiogenesis in MI. In the present study the role of endostatin in left ventricular (LV) remodeling and heart failure was tested in a rat MI model.
When exposed to hypoxia, rat cardiomyocytes showed increased expression of endostatin. After MI induction in the rat MI model, endostatin expression was upregulated in cardiomyocytes, and serum endostatin levels were significantly elevated. Anti-endostatin antibody treatment resulted in significantly higher mortality of MI rats than controls. The MI rats with endostatin neutralization displayed adverse LV remodeling and severe heart failure compared with control MI rats. Although angiogenesis was increased, tissue remodeling and interstitial fibrosis were further exaggerated in post-MI hearts by endostatin neutralization. Furthermore, the expression and protease activity of matrix metalloproteinases -2 and -9, and of angiotensin-converting enzyme were markedly elevated by endostatin neutralization.
Neutralization of endostatin worsens the symptoms and outcomes of MI in a rat model. The results imply that endogenous endostatin/collagen XVIII may suppress aberrant LV remodeling and heart failure after MI. (Circ J 2010; 74: 109 - 119).
尽管治疗性血管生成是治疗心肌梗死（MI）最有前途的策略，但内源性血管生成抑制剂（如内皮抑素）是否以及如何调节 MI 中的血管生成仍不清楚。本研究在大鼠 MI 模型中检测了内皮抑素在左心室（LV）重构和心力衰竭中的作用。
当暴露于缺氧时，大鼠心肌细胞中内皮抑素的表达增加。在大鼠 MI 模型中诱导 MI 后，心肌细胞中内皮抑素的表达上调，血清内皮抑素水平显著升高。抗内皮抑素抗体治疗导致 MI 大鼠的死亡率明显高于对照组。与对照 MI 大鼠相比，内皮抑素中和的 MI 大鼠表现出不良的 LV 重构和严重的心衰。尽管血管生成增加，但内皮抑素中和进一步加剧了 MI 后组织重构和间质纤维化。此外，基质金属蛋白酶-2 和-9 的表达和蛋白酶活性以及血管紧张素转换酶在内皮抑素中和时明显升高。
中和内皮抑素会加重大鼠 MI 模型的症状和结局。结果表明，内源性内皮抑素/胶原 XVIII 可能抑制 MI 后异常的 LV 重构和心力衰竭。（Circ J 2010; 74: 109 - 119）。
