Nuclear plakoglobin is essential for differentiation of cardiac progenitor cells to adipocytes in arrhythmogenic right ventricular cardiomyopathy.
Nuclear plakoglobin is essential for differentiation of cardiac progenitor cells to adipocytes in arrhythmogenic right ventricular cardiomyopathy.
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DOI：
10.1161/circresaha.111.255075
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发表时间：
2011-12-09
影响因子：
20.1
通讯作者：
Marian AJ
中科院分区：
文献类型：
--
作者：
Lombardi R;da Graca Cabreira-Hansen M;Bell A;Fromm RR;Willerson JT;Marian AJ
致心律失常性右心室心肌病（ARVC）是一种以心肌纤维脂肪形成为特征的桥粒蛋白疾病。我们已经暗示连接蛋白斑珠蛋白（PG）的信号转导特性在ARVC的发病机制。阐明PG在ARVC脂肪形成中的致病作用。我们产生了过度表达PG的小鼠，无论是野生型（PGWT）还是截短型（PGTR），已知会导致心脏中的ARVC;以及PG null（PG−/−）胚胎。PGWT和PGTR小鼠表现出纤维性肥胖、心功能障碍和过早死亡。亚细胞蛋白分级和免疫荧光显示PGWT和PGTR的核定位和减少PGTR的膜定位。免疫共沉淀显示PGTR与桥粒蛋白DSP和DSG 2的结合减少，但PGWT与桥粒蛋白DSP和DSG 2的结合不减少。用荧光激活细胞分选法从PGWT和PGTR的心脏中分离出c-Kit+：Sca 1+心脏祖细胞（CPC），并在CPC中表达转基因PGWT和PGTR。从转基因心脏中分离的CPC显示脂肪形成增强，脂肪形成因子KLF 15、C/EBP-α和非经典Wnt 5 b水平升高，而脂肪形成抑制剂CTGF水平降低。BIO处理激活了经典Wnt信号传导，逆转了前脂肪形成转录开关，并以剂量依赖性方式阻止脂肪形成。此外，从PG−/−胚胎中分离的c-Kit+ CPC对脂肪形成具有抗性，表达高水平的CTGF和其他典型Wnt信号传导靶点。核PG通过抑制经典Wnt信号传导和诱导前脂肪形成基因表达而引起c-Kit+ CPC中的脂肪形成。研究结果表明，ARVC中的脂肪细胞至少部分来源于c-Kit+ CPC。
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease of desmosome proteins characterized by fibroadipogenesis in the myocardium. We have implicated signaling properties of junction protein plakoglobin (PG) in the pathogenesis of ARVC. To delineate the pathogenic role of PG in adipogenesis in ARVC. We generated mice overexpressing PG, either a wildtype (PGWT) or a truncated (PGTR), known to cause ARVC, in the heart; and PG null (PG−/−) embryos. PGWT and PGTR mice exhibited fibro-adiposis, cardiac dysfunction, and premature death. Subcellular protein fractionation and immunofluorescence showed nuclear localization of PGWT and PGTR and reduced membrane localization of PGTR. Coimmunoprecipitation showed reduced binding of PGTR but not PGWT to desmosome proteins DSP and DSG2. Transgene PGWT and PGTR were expressed in c-Kit+:Sca1+ cardiac progenitor cells (CPCs) isolated from the hearts of PGWT and PGTR by fluorescence activated cell sorting. CPCs isolated from the transgenic hearts showed enhanced adipogenesis, increased levels of adipogenic factors KLF15, C/EBP-α and noncanonical Wnt5b, and reduced level of CTGF, an inhibitor of adipogenesis. Treatment with BIO activated the canonical Wnt signaling, reversed the proadipogenic transcriptional switch and prevented adipogenesis in a dose-dependent manner. Moreover, c-Kit+ CPCs, isolated from PG−/− embryos, were resistant to adipogenesis, expressed high mRNA levels of CTGF and other canonical Wnt signaling targets. Nuclear PG provokes adipogenesis in c-Kit+ CPCs by repressing the canonical Wnt signaling and inducing a proadipogenic gene expression. The findings suggest that adipocytes in ARVC, at least in part, originate from c-Kit+ CPCs.