Cardiac ISL1-Interacting Protein, a Cardioprotective Factor, Inhibits the Transition From Cardiac Hypertrophy to Heart Failure.
Cardiac ISL1-Interacting Protein, a Cardioprotective Factor, Inhibits the Transition From Cardiac Hypertrophy to Heart Failure.
复制标题
心脏 ISL1 相互作用蛋白是一种心脏保护因子，可抑制心脏肥大向心力衰竭的转变
DOI：
10.3389/fcvm.2022.857049
复制
发表时间：
2022
影响因子：
3.6
通讯作者：
Huang ZP
中科院分区：
文献类型：
--
作者：
Yan Y;Long T;Su Q;Wang Y;Chen K;Yang T;Zhao G;Ma Q;Hu X;Liu C;Liao X;Min W;Li S;Zhang D;Yang Y;Pu WT;Dong Y;Wang DZ;Chen Y;Huang ZP
心力衰竭的特征是心脏无法有效泵血并产生适当的血液循环来满足身体的需要；这是一种毁灭性的疾病，影响着全球1亿多人。尽管如此，人们对心肌肥厚向心力衰竭转变的调控机制知之甚少。在此之前，我们发现了一个心肌细胞丰富的基因，CIP，它在病理刺激下调节心脏的动态平衡。在这里，我们发现心脏转录因子GATA4结合CIP基因的启动子并调节其表达。我们进一步确定，在患病的人心脏中，CIP的mRNA和蛋白都减少了。在小鼠模型中，在心肌肥厚建立后诱导心脏特异性CIP的过度表达，通过抑制疾病向心力衰竭的进展来保护心脏。转录组分析表明，胰岛素样生长因子、mTORC2和转化生长因子β信号通路介导了环磷酰胺抑制病理性心脏重构的作用。我们的研究证实了GATA4是心肌细胞CIP基因表达的上游调节因子，以及CIP表达在人类心脏病中的临床意义。更重要的是，我们的研究表明，CIP是从心肌肥厚向心力衰竭转变的关键调节因子。CIP在心力衰竭发病过程中的干预能力为预防心脏病进展提供了一条新的治疗途径。
Heart failure is characterized by the inability of the heart to pump effectively and generate proper blood circulation to meet the body’s needs; it is a devastating condition that affects more than 100 million people globally. In spite of this, little is known about the mechanisms regulating the transition from cardiac hypertrophy to heart failure. Previously, we identified a cardiomyocyte-enriched gene, CIP, which regulates cardiac homeostasis under pathological stimulation. Here, we show that the cardiac transcriptional factor GATA4 binds the promotor of CIP gene and regulates its expression. We further determined that both CIP mRNA and protein decrease in diseased human hearts. In a mouse model, induced cardiac-specific overexpression of CIP after the establishment of cardiac hypertrophy protects the heart by inhibiting disease progression toward heart failure. Transcriptome analyses revealed that the IGF, mTORC2 and TGFβ signaling pathways mediate the inhibitory function of CIP on pathologic cardiac remodeling. Our study demonstrates GATA4 as an upstream regulator of CIP gene expression in cardiomyocytes, as well as the clinical significance of CIP expression in human heart disease. More importantly, our investigation suggests CIP is a key regulator of the transition from cardiac hypertrophy to heart failure. The ability of CIP to intervene in the onset of heart failure suggests a novel therapeutic avenue of investigation for the prevention of heart disease progression.
登录
查看更多内容
DOI：
10.1073/pnas.1016959108
发表时间：
2011-04-05
影响因子：
11.1
作者：
He, Aibin;Kong, Sek Won;Pu, William T.
通讯作者：
Pu, William T.
影响因子：
15.9
作者：
Schultz, JEJ;Witt, SA;Doetschman, T
通讯作者：
Doetschman, T
DOI：
10.1074/jbc.m110.165548
发表时间：
2011-06-03
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Ahmady E;Deeke SA;Rabaa S;Kouri L;Kenney L;Stewart AF;Burgon PG
通讯作者：
Burgon PG
影响因子：
3.7
作者：
Cortés R;Rivera M;Roselló-Lletí E;Martínez-Dolz L;Almenar L;Azorín I;Lago F;González-Juanatey JR;Portolés M
通讯作者：
Portolés M
影响因子：
11.4
作者：
Nakae, J;Barr, V;Accili, D
通讯作者：
Accili, D