Department of Medicine, University of California-San Diego, La Jolla, 92093, USA.
Circ Res. 2012 Feb 3;110(3):456-64. doi: 10.1161/CIRCRESAHA.111.258616. Epub 2011 Dec 8.
Thymosin beta 4 (Tβ4) is a 43-amino acid factor encoded by an X-linked gene. Recent studies have suggested that Tβ4 is a key factor in cardiac development, growth, disease, epicardial integrity, and blood vessel formation. Cardiac-specific short hairpin (sh)RNA knockdown of tβ4 has been reported to result in embryonic lethality at E14.5-16.5, with severe cardiac and angiogenic defects. However, this shRNA tβ4-knockdown model did not completely abrogate Tβ4 expression. To completely ablate Tβ4 and to rule out the possibility of off-target effects associated with shRNA gene silencing, further studies of global or cardiac-specific knockouts are critical.
We examined the role of Tβ4 in developing and adult heart through global and cardiac specific tβ4-knockout mouse models.
Global tβ4-knockout mice were born at mendelian ratios and exhibited normal heart and blood vessel formation. Furthermore, in adult global tβ4-knockout mice, cardiac function, capillary density, expression of key cardiac fetal and angiogenic genes, epicardial marker expression, and extracellular matrix deposition were indistinguishable from that of controls. Tissue-specific tβ4-deficient mice, generated by crossing tβ4-floxed mice to Nkx2.5-Cre and αMHC-Cre, were also found to have no phenotype.
We conclude that Tβ4 is dispensable for embryonic viability, heart development, coronary vessel development, and adult myocardial function.
胸腺素β 4（Tβ4）是一种由 X 连锁基因编码的 43 个氨基酸因子。最近的研究表明，Tβ4 是心脏发育、生长、疾病、心外膜完整性和血管形成的关键因素。已有研究报道，心脏特异性短发夹（sh）RNA 敲低 tβ4 会导致胚胎在 E14.5-16.5 时致死，伴有严重的心脏和血管生成缺陷。然而，这种 shRNA tβ4 敲低模型并没有完全消除 Tβ4 的表达。为了完全消除 Tβ4，并排除 shRNA 基因沉默相关的脱靶效应的可能性，进一步研究心脏特异性或全身性敲除是至关重要的。
通过心脏特异性和全身性 tβ4 敲除小鼠模型，研究 Tβ4 在心脏发育和成年心脏中的作用。
全身性 tβ4 敲除小鼠以孟德尔比率出生，表现出正常的心脏和血管形成。此外，在成年全身性 tβ4 敲除小鼠中，心脏功能、毛细血管密度、关键心脏胎儿和血管生成基因的表达、心外膜标志物的表达和细胞外基质沉积与对照组无明显差异。通过将 tβ4 基因敲除小鼠与 Nkx2.5-Cre 和αMHC-Cre 杂交，生成了心脏特异性 tβ4 缺陷型小鼠，也未发现表型。
我们得出结论，Tβ4 对于胚胎存活、心脏发育、冠状动脉发育和成年心肌功能是可有可无的。
