Tomita H, Egashira K, Ohara Y, Takemoto M, Koyanagi M, Katoh M, Yamamoto H, Tamaki K, Shimokawa H, Takeshita A
Research Institute of Angiocardiology and the Second Department of Internal Medicine, Kyushu University Faculty of Medicine, Fukuoka, Japan.
Hypertension. 1998 Aug;32(2):273-9. doi: 10.1161/01.hyp.32.2.273.
We previously reported that the chronic inhibition of nitric oxide (NO) synthesis increases cardiac tissue angiotensin-converting enzyme expression and causes cardiac fibrosis in rats. However, the mechanisms are not known. Transforming growth factor-beta (TGF-beta) is a key molecule that is responsible for tissue fibrosis. The present study investigated the role of TGF-beta in the pathogenesis of cardiac fibrosis. The development of cardiac fibrosis by oral administration of the NO synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) to normal rats was preceded by increases in mRNA levels of cardiac TGF-beta1 and extracellular matrix (ECM) proteins. TGF-beta immunoreactivity was increased in the areas of fibrosis. Treatment with a specific angiotensin II type 1 receptor antagonist, but not with hydralazine, completely prevented the L-NAME-induced increases in the gene expression of TGF-beta1 and ECM proteins and also prevented cardiac fibrosis. Intraperitoneal injection of neutralizing antibody against TGF-beta did not affect the L-NAME-induced increase in TGF-beta1 mRNA levels but prevented an increase in the mRNA levels of ECM protein. These results suggest that the early induction of TGF-beta1 via the angiotensin II type 1 receptor plays a major role in the development of cardiac fibrosis in this model.
我们之前报道过，慢性抑制一氧化氮（NO）合成会增加大鼠心脏组织中血管紧张素转换酶的表达并导致心脏纤维化。然而，其机制尚不清楚。转化生长因子-β（TGF-β）是导致组织纤维化的关键分子。本研究调查了TGF-β在心脏纤维化发病机制中的作用。给正常大鼠口服NO合成抑制剂N（ω）-硝基-L-精氨酸甲酯（L-NAME）导致心脏纤维化的过程中，心脏TGF-β1和细胞外基质（ECM）蛋白的mRNA水平先升高。在纤维化区域，TGF-β免疫反应性增强。用特异性血管紧张素II 1型受体拮抗剂治疗可完全阻止L-NAME诱导的TGF-β1和ECM蛋白基因表达增加，也可预防心脏纤维化，而用肼屈嗪治疗则无此效果。腹腔注射抗TGF-β中和抗体不影响L-NAME诱导的TGF-β1 mRNA水平升高，但可阻止ECM蛋白mRNA水平升高。这些结果表明，在该模型中，通过血管紧张素II 1型受体早期诱导TGF-β1在心脏纤维化的发展中起主要作用。
