GATA4基因H435Y位点突变对小鼠心功能的影响

目的:研究GATA4基因H435Y位点突变对小鼠心功能的影响以及可能机制。方法:随机选取野生型(WT)小鼠和GATA4基因H435Y位点突变(Gata4 H435Y)小鼠各6只,检测和比较两组小鼠的心功能和心脏重量/体重比,应用Masson染色观察小鼠心肌组织形态,实时定量反转录聚合酶链式反应(qRT-PCR)和蛋白免疫印迹(Western blot)分别检测心肌组织中Gata4、Sox9、Scleraxis、Tenascin和Aggrecan的m RNA和蛋白表达水平。结果:与WT组小鼠相比,GATA4 H435Y组小鼠左心室射血分数(LVEF)和左心室缩短分数(LVFS)降低(P0.05),左心室收缩末期内径(LVIDs)增大(P0.05)。两组组小鼠的心脏重量比较差异无统计学意义(P0.05),GATA4 H435Y组小鼠体重较WT组小鼠显著减轻、心重/体重比明显减小(P0.05)。Masson染色结果显示两组小鼠心肌纤维无明显差异,但WT组小鼠心肌胶原纤维染色较深。与WT组小鼠相比较,GATA4 H435Y组小鼠心肌组织中GATA4、Scleraxis和Sox9的m RNA及蛋白明显表达下降(P0.05),Aggrecan和TenascinmRNA和蛋白表达均无明显统计学差异(p0.05)。结论:GATA4基因H435Y位点突变可能通过降低GATA4及下游基因表达,影响心肌细胞外基质基因的表达,进而损害小鼠的心功能。     

G790del mutation in DSC2 alone is insufficient to develop the pathogenesis of ARVC in a mouse model

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease that causes heart failure and/or sudden cardiac death. Several desmosomal genes (DSC2, PKG, PKP2, DSP, and RyR2) are thought to be the causative gene involved in ARVC. Out of them, DSC2 mutations account for 2% of ARVC genetic abnormalities. This study aimed to clarify the effect of G790del mutation in DSC2 on the arrhythmogenic mechanism and cardiac function in a mouse model.ResultNeither the heterozygous +/G790del nor homozygous G790del/G790del mice showed structural and functional defects in the right ventricle (RV) or lethal arrhythmia. The homozygous G790del/G790del 6-month-old mice slightly showed left ventricular (LV) dysfunction. Cell shortening decreased with prolongation of intracellular Ca2+ transient in cardiomyocytes isolated from the homozygous G790del/G790del mice, and spontaneous Ca²⁺ transients were frequently observed in response to isoproterenol.ConclusionsG790del mutation in DSC2 was not relevant to the pathogenesis of ARVC, but showed a slight contractile dysfunction and Ca²⁺ dysregulation in the LV.     

Bmp2 and Bmp4 genetically interact to support multiple aspects of mouse development including functional heart development

Bone morphogenetic proteins (BMPs) have multiple roles during embryogenesis. Current data indicate that the dosage of BMPs is tightly regulated for normal development in mice. Since Bmp2 or Bmp4 homozygous mutant mice show early embryonic lethality, we generated compound heterozygous mice for Bmp2 and Bmp4 to explore the impact of lowered dosage of these BMP ligands. Genotyping pups bred between Bmp2 and Bmp4 heterozygous mice revealed that the ratio of adult compound heterozygous mice for Bmp2 and Bmp4 is much lower than expected. During embryogenesis, the compound heterozygous embryos showed several abnormalities, including defects in eye formation, body wall closure defects, and ventricular septal defects (VSD) in the heart. However, the ratio of the compound heterozygous embryos was the same as expected. Caesarean sections at E18.5 revealed that half of the compound heterozygotes died soon after birth, and the majority of the dead individuals exhibited VSD. Survivors were able to grow to adults, but their body weight was significantly lower than control littermates. They demonstrated progressive abnormalities in the heart, eventually showing a branched leaflet in atrioventricular valves. These results suggest that the dosage of both BMP2 and 4 is critical for functional heart formation during embryogenesis and after birth. genesis 47:374–384, 2009. © 2009 Wiley‐Liss, Inc.     

Cardiac abnormalities cause early lethality of jumonji mutant mice

jumonji (jmj) mutant mice, obtained by a gene trap strategy, showed several morphological abnormalities including neural tube and cardiac defects, and died in utero around embryonic day 11.5 (E11.5). It is unknown what causes the embryonic lethality. Here, we demonstrate that exogenous expression of jmj gene in the heart of jmj mutant mice rescued the morphological phenotypes in the heart, and these embryos survived until E13.5. These results suggest that there are at least two lethal periods in jmj mutant mice, and that cardiac abnormalities may cause the earlier lethality. In addition, the rescue of the cardiac abnormalities by the jmj transgene provided solid evidence that the cardiac abnormalities resulted from mutation of the jmj gene.