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Generation of sarcolipin heart-specific transgenic mice and molecular mechanism of atrial chamber-specific expression

肌磷脂心脏特异性转基因小鼠的产生及心房特异性表达的分子机制

基本信息

批准号：
15500288
负责人：
MINAMISAWA Susumu
金额：
$ 2.3万
依托单位：
Yokohama 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：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

I. Cardiac dysfunction sarcolipin heart-specific transgenic miceIn vivo echocardiography and hemodynamic study demonstrated that cardiac function, especially diastolic function was impaired in sarcolipin (SLN) heart-specific transgenic mice when compared with those in age-matched control mice. Although SIN heart-specific transgenic mice did not exhibited either cardiac hypertrophy or dilation, molecular markers of cardiac hypertrophy such as ANF and BNP were up regulated, suggesting masked cardiac remodeling in SLN heart-specific transgenic mine. These data indicate that SLN play an important role in atrial function via regulation of SERCA2a activity.II. Anaiysisi of mouse sarcolipin promoter and its transcriptional regulationWe cloned a 2.3-kilobase pair DNA fragment encompassing the 5'-flanking region of the mouse SLN gene and examined the effect of retinoic acid on its promoter activity. Transient transfection of H9C2 with F1-luciferase (-2237 to +62 nucleotides) yielded a 40-fold increase in promoter activity. Transient transfection of a series of 5'→3' deletion constructs of F1-luciferase suggested that the minimal region for full activation of the SLN promoter activity is located up to -326 nucleotides and that negative regulatory elements of RA were located between -2237 and -326 nucleotides. The present data indicate that the expression of SLN mRNA is likely regulated by retinoic acid, at least in part, at transcriptional level. In addition, we found that pressure overload, retinoic acid and thyroid hormono down-regulated the expression of SLN mRNAs.

I.心肌特异性转基因鼠心功能障碍的研究心肌特异性转基因鼠心脏特异性转基因鼠心功能障碍的研究虽然SIN心脏特异性转基因小鼠没有表现出心脏肥大或扩张，但心脏肥大的分子标志物如ANF和BNP上调，表明SLN心脏特异性转基因小鼠的心脏重塑被掩盖。这些数据表明SLN通过调节SERCA 2a活性在心房功能中发挥重要作用。本研究克隆了小鼠肌磷脂基因5 ′侧翼区的2.3-磷酸酶对DNA片段，并研究了视黄酸对其启动子活性的影响。用F1-荧光素酶（-2237至+62个核苷酸）瞬时转染H9 C2产生启动子活性的40倍增加。瞬时转染一系列5 '→ 3'缺失的F1-荧光素酶构建体表明，SLN启动子活性完全激活的最小区域位于-326个核苷酸，RA的负调控元件位于-2237和-326个核苷酸之间。目前的数据表明，SLN mRNA的表达可能是由视黄酸，至少部分，在转录水平上进行调节。此外，我们还发现压力超负荷、维甲酸和甲状腺激素可下调SLN mRNA的表达。