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The pathophysiology of cardiac and vascular remodeling and gene therapy

心脏和血管重塑的病理生理学和基因治疗

基本信息

批准号：
12670684
负责人：
YOSHIYAMA Minoru
金额：
$ 2.05万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Inhibition of the renin-angiotensin system has been shown to prevent left ventricular remodeling after myocardial infarction. However, the effect of angiotensin on the signal transduction pathway of left ventricular remodeling after myocardial infarction is as yet unknown. ACE inhibitor and ARB inhibited JNKs, NF-kappa B and AP-1 activities. Increased JNKs, AP-1, NF- kappa B, and Sp-1 DNA-binding activities were suppressed by both drugs in the infarcted region. Doppler-echocardiography showed that ACE inhibitor and ARB prevented the dilatation of left ventricular cavity at 14 days and improved diastolic filling pattern. JNKs, AP-1 and NF- kappa B activation in myocardial infarcted rats could be responsible for left ventricular remodeling after myocardial infarction and angiotensin may be related to the activation of these signals.The activator protein 1 (AP-1) transcriptional complex, containing Jun and Fos proteins, is involved in regulating many cellular processes such as proliferation and differentiation. However, little is known about a direct relationship between AP -1 activities and cardiomyocyte hypertrophy. To elucidate the roles of myocardial AP-1 activities, dominant negative mutant of c-Jun (DNJun) was overexpressed in cultured rat neonatal ventricular myocytes by adenovirus vector to abrogate endogenous AP-1 activation. Both endothelin 1 and phenylephrine significantly enhanced AP-1 DNA binding Adenovirus carrying DNJun prevented the transcriptional activation of the AP -1 by ET and PE, using AP-1 reporter enzyme firefly luciferase assay. Moreover, DNJun prevented the increase in incorporation of (3)H -phenylalanine, cell size, and the mRNA expression of ANP and BNP by ET and PE. We provide the first evidence that DNJun inhibits cardiomyocyte hypertrophy through inhibition of AP-1 transcriptinal activity.

抑制肾素-血管紧张素系统已被证明可以防止心肌梗死后左心室重构。然而，血管紧张素对心肌梗死后左室重构信号转导通路的影响尚不清楚。ACE抑制剂和ARB抑制JNKs、nf - κ B和AP-1活性。两种药物均抑制梗死区JNKs、AP-1、NF- κ B和Sp-1 dna结合活性的升高。多普勒超声心动图显示，ACE抑制剂和ARB在第14天阻止左室腔扩张，改善舒张充盈模式。心肌梗死大鼠JNKs、AP-1和NF- kappa B的激活可能与心肌梗死后左室重构有关，血管紧张素可能与这些信号的激活有关。激活蛋白1 （AP-1）转录复合体，包含Jun和Fos蛋白，参与调节许多细胞过程，如增殖和分化。然而，对于AP -1活性与心肌细胞肥大之间的直接关系知之甚少。为了阐明心肌AP-1活性的作用，利用腺病毒载体在培养的大鼠新生心室肌细胞中过表达c-Jun显性阴性突变体（DNJun），以消除内源性AP-1的激活。通过AP-1报告酶萤火虫荧光素酶测定，内皮素1和苯肾上腺素均能显著增强AP-1 DNA结合腺病毒携带DNJun，阻止ET和PE对AP-1的转录激活。此外，DNJun抑制了ET和PE对(3)H -苯丙氨酸掺入、细胞大小以及ANP和BNP mRNA表达的增加。我们提供了DNJun通过抑制AP-1转录活性抑制心肌细胞肥大的第一个证据。