| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
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
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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
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