Role of ASK1 in Molecular Mechanism of Cardiovascular Diseases

细胞凋亡信号调节蛋白1是一种丝氨酸-苏氨酸激酶，在细胞的凋亡、存活和分化中起着关键作用。因此，我们研究了ASK1在心血管疾病中的可能作用。我们给大鼠注射血管紧张素II，以研究ASK1在心肌肥厚中的作用。用腺病毒载体将ASK1基因转移到心肌组织进行显性负性突变，检测其对心肌墨汁和P38活性、心肌肥大和基因表达的影响。我们发现，显性阴性ASK1的腺病毒感染显著地阻止了血管紧张素II诱导的病理性心肌肥厚。此外，我们还利用ASK1缺陷小鼠研究了ASK1在心脏病中的作用。向野生型小鼠注射血管紧张素II可导致JNK和P38激活、心肌肥大、心脏表型和重塑相关基因表达、间质纤维化和冠状动脉重塑。而所有这些影响…在ASK1缺乏的小鼠中，野生型小鼠的血管紧张素II水平显著降低。这些结果表明，ASK1在血管紧张素II诱导的病理性心肌肥大中起关键作用。除了ASK1在心脏病中的作用外，我们还研究了ASK1在血管疾病中的作用。ASK1显性负突变基因转移到大鼠颈动脉可显著阻止球囊损伤诱导的血管平滑肌细胞的增殖和迁移，从而显著预防血管内膜增生。ASK1显性负性突变体的这种抑制作用是通过抑制JNK和P38的激活来实现的。此外，我们利用ASK1缺陷小鼠研究了ASK1在血管重塑中的作用。野生型小鼠股动脉袖套损伤后血管内膜明显增厚，ASK1基因缺陷小鼠血管内膜增生明显减轻。我们还比较了ASK1缺陷小鼠和野生型小鼠的血管平滑肌细胞的增殖和迁移。我们注意到ASK1缺陷小鼠的血管平滑肌细胞的增殖和迁移明显低于野生型小鼠。这些结果表明ASK1参与了血管重塑。因此，ASK1与心血管疾病的分子机制有关，有望成为心血管疾病的治疗靶点。较少

Apoptosis signal-regulated kinase 1 is a serine-threonine kinase, which plays a pivotal role in cell apoptosis, survival, and differentiation. Therefore, we investigated the possible role of ASK1 in cardiovascular diseases. We infused angiotensin II to rats, to study the role of ASK1 in cardiac hypertrophy. Dominant negative mutant of ASK1 gene transfer to cardiac tissue was performed with adenoviral vector and we examined the effect on cardiac INK and P38 activities, and cardiac hypertrophy and gene expression. We found that adenoviral infection of dominant negative ASK1 significantly prevented angiotensin II-induced pathologic cardiac hypertrophy. Furthermore, we also investigated the contribution of ASK1 to cardiac disease, using ASK1 deficient mice. Angiotensin II infusion to wild type mice caused activation of JNK and P38, cardiac hypertrophy, cardiac phenotype-and remodeling-associated gene expression, interstitial fibrosis, and coronary arterial remodeling. And all these effects … More of angiotensin II in wild type mice were significantly lessened in ASK1 deficient mice. These results show that ASK1 plays the crucial role in pathologic cardiac hypertrophy induced by angiotensin II. Besides the role of ASK1 in cardiac disease, we studied the contribution of ASK1 to vascular disease. Gene transfer of dominant negative mutant of ASK1 to rat carotid artery significantly prevented balloon injury-induced vascular smooth muscles cell proliferation and migration, leading to the significant prevention of vascular intimal hyperplasia. This inhibitory effect of dominant negative mutant of ASK1 on intimal hyperplasia was mediated by inhibition of JNK and P38 activations. Furthermore, we investigated the role of ASK1 in vascular remodeling, using ASK1 deficient mice. Cuff injury of femoral artery in wild type mice induced the significant thickening of vascular intimal and this intimal hyperplasia in wild type mice was significantly reduced in ASK1 deficient mice. We also compared between vascular smooth muscle cells from ASK1 deficient mice and wild type mice, regarding proliferation and migration. We noted that the proliferation and migration of vascular smooth muscle cells from ASK1 deficient mice were significantly decreased compared with those from wild type mice. These results indicate that ASK1 is implicated in vascular remodeling. Thus, ASK1 is responsible for the molecular mechanism of cardiovascular diseases and seems to be the promising therapeutic target for cardiovascular disease. Less