The pathophysiology of cardiac and vascular remodeling and gene therapy

抑制肾素-血管紧张素系统已被证明可以预防心肌梗死后的左室重构。然而，血管紧张素在心肌梗死后左室重构的信号转导通路中的作用尚不清楚。ACE抑制剂和ARB抑制JNKs、NF-kappaB和AP-1的活性。两种药物均可抑制梗死区JNKs、AP-1、NF-kappaB和Sp-1DNA结合活性的升高。超声心动图显示血管紧张素转换酶抑制剂和血管紧张素转换酶抑制剂在第14天阻止了左室腔扩张，改善了舒张期充盈模式。心肌梗死大鼠心肌梗死后JNKs、AP-1和NF-kappaB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，参与调控细胞增殖和分化等多个过程。然而，AP-1活性与心肌细胞肥大之间的直接关系知之甚少。为阐明心肌AP-1活性的作用，用腺病毒载体在培养的新生大鼠心肌细胞中过表达显性负性c-jun突变体(DNJun)，以阻断内源性AP-1的激活。AP-1报告酶萤火素酶检测显示，内皮素1和苯肾上腺素均能显著增强携带DNJun的AP-1DNA结合腺病毒对AP-1转录激活的抑制作用。此外，DNJun还可抑制ET和PE引起的(3)H-苯丙氨酸掺入、细胞大小和ANP、BNP基因表达的增加。我们首次提供了DNJun通过抑制AP-1转录活性来抑制心肌细胞肥大的证据。

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.