Adrenomedullin and Vasculitis, Study with Knock Out Mouse
Objectives Adrenomedullin(AM) is not only a potent vasodilator but also regulates several hormone release such as aldosterone, NO and also regulates inflammatory reactions. In order to clarify its physiological role, we generated AM knock-out mouse and investigated its cardiac and vascular changes. Method A point mutation to stop AM translation were induced and by conventional method, AM knock-out mouse was generated. As homozygote was lethal we used heterozygote for this study. In heterozygote plasma and tissue AM level were as half as wild type. Angiotensin II were continuously administered and 8% NaCl diet were loaded to 8 weeks old male heterozygote and wild type for 2 weeks. In some mice, we wrapped silicone tube around the femoral artery and transferred adrenomedullin gene via adenovirus vector topically. Blood pressure were monitored by tail cuff method. After 2 weeks, heart weight were measured and pathological changes were observed. Results Baseline SBP were comparable between heterozygote and wild type (150±10 mmHg vs 142±8 mmHg). One week after angiotensin II and salt loading both mice increased blood pressure to 170±9 mmHg in heterozygote and 168±10 mmHg in wild type. At the end of the study SBP of heterozygote were 160±13 mmHg and that of wild type were 173±9 mmHg. Heart weight/BW were significantly larger in heterozygote (0.0068±0.0003) than in wild (0.0061±0.0002). Perivascular area of coronary artery from heterozygote was full of inflammatory cells and fibrosis. In severe case, coronary aretery showed fibrinoid necrosis. These findings were not found in kidney or other arterioles.The femoral artery from heterozygote showed marked medial proliferation and stenosis compared to wild type. And this change was rescued by AM administration. Conclusion AM is protective against coronary artery injury and cardiomegaly.