Expression Profiling of Heart (NH, TAC and TAC-R)

Transverse aortic constriction (TAC) is a well-established method for studying the pathomechanisms of heart failure in animal models of cardiac hypertrophy. A number of studies have shown that the treatment of heart failure in this animal model of cardiac hypertrophy suggests that hypertrophy and fibrosis may be reversible. However, since TAC-release protocols that improve hemodynamics by releasing physical stenosis remain undefined, the histological characteristics and molecular biological regulatory mechanisms of the reversibility of cardiac hypertrophy and fibrosis are unknown. Therefore, this study aimed to establish a TAC release model and investigate the reversibility and plasticity mechanisms of myocardial hypertrophy, fibrosis, and angiogenesis. Four weeks post-TAC surgery, TAC release was conducted by cutting the aortic stenosis sutures. The TAC group exhibited severe myocardial hypertrophy, fibrosis, and increased angiogenesis, along with diastolic dysfunction. Conversely, the TAC-release group showed reduced hypertrophy and fibrosis, and improved diastolic function. Gene expression analysis highlighted Regulator of Calcineurin 1 as a key player in cardiac function and histological changes post-TAC release. Rcan1 knockdown exacerbated myocardial hypertrophy and fibrosis in the TAC-release group. This study sheds light on the functional, structural, and histological changes in the heart induced by TAC release and elucidates some of its regulatory mechanisms.主动脉弓缩窄术（Transverse aortic constriction, TAC）是研究心脏肥大动物模型中心力衰竭病理机制的经典实验方法。已有多项研究借助该心脏肥大动物模型开展心力衰竭相关干预实验，结果提示心肌肥大与纤维化具备可逆性。然而，由于通过解除物理狭窄以改善血流动力学的TAC释放方案仍未明确，心脏肥大与纤维化可逆性的组织学特征及分子生物学调控机制尚不明确。为此，本研究旨在构建TAC释放模型，并探究心肌肥大、纤维化及血管生成的可逆性与可塑性调控机制。于TAC术后4周，通过剪断主动脉狭窄缝合线完成TAC释放操作。TAC组小鼠呈现严重心肌肥大、纤维化及血管生成增加，并伴随舒张功能障碍。与之相对，TAC释放组的心肌肥大与纤维化程度显著减轻，舒张功能亦得到改善。基因表达分析结果显示，钙调神经磷酸酶调节因子1（Regulator of Calcineurin 1，后文简称Rcan1）是TAC释放后心脏功能与组织学变化的关键调控因子。在TAC释放组中敲低Rcan1，会进一步加剧心肌肥大与纤维化程度。本研究阐明了TAC释放诱导的心脏功能、结构及组织学变化，并揭示了其部分调控机制。