CIP, a cardioprotective factor, inhibits the transition from cardiac hypertrophy to heart failure

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 forthe prevention of heart disease progression. RNA-seq of CIP-OE mouse heart after 8 weeks of TAC operation. "KI" refered to CIP overexpression (CIP-OE) mice. CIP-KI-flox mice, which have a Rosa-CIP allele (the stop codon is present and floxed) were bred with aMHC-Mer-Cre-Mer mice to obtain CIP-OE (CIP-KI-flox;aMHC-Mer-Cre-Mer) mouse. Tamoxifen was administrated through intraperitoneal injection to activate the expression of Cre recombinase and the excision of the stop codon for the ectopic expression of CIP transgene in the heart in CIP-OE mice. “Ctrl” refered to CIP-KI-flox littermates.