Cardiac ISL1-Interacting Protein, a Cardioprotective Factor, Inhibits the Transition From Cardiac Hypertrophy to Heart Failure

Frontiers in Cardiovascular Medicine

Qing Ma¹  Xiaoyun Hu¹  Yi Wang¹  Da-Zhi Wang¹  William T. Pu¹  Wang Min²  Dihua Zhang³  Yuedong Yang⁴  Ken Chen⁴  Guangyin Zhao⁵  Qiao Su⁵  Tiqun Yang⁶  Youchen Yan⁶  Tianxin Long⁶  Chen Liu⁶  Shujuan Li⁶  Xinxue Liao⁶  Yugang Dong⁶  Yili Chen⁶  Zhan-Peng Huang⁷ 

[1] Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States;Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;Key Laboratory of Machine Intelligence and Advanced Computing, Ministry of Education, Sun Yat-sen University, Guangzhou, China;Laboratory Animal Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China;National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, China;School of Data and Computer Science, Sun Yat-sen University, Guangzhou, China;

关键词: heart failure;    cardiac hypertrophy;    CIP;    gene regulation;    cardiac remodeling;   

DOI  :  10.3389/fcvm.2022.857049

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown