CNOT6L deadenylase suppresses cardiac remodeling in heart failure through downregulation of tenascin-C mRNA.

Heart failure is rapidly increasing and is a growing burden on human health and the economy in the world. The functional role of mRNA regulation in the pathogenesis of heart failure remains to be elucidated. Carbon catabolite repression 4-negative on TATA-less complex is a multisubunit protein complex that deadenylates mRNA, a process of exonuclease-mediated degradation of mRNA poly(A) tail. Here we show the cardiac protective roles of deadenylase subunit CNOT6L against cardiac stress. After 2 weeks of transverse aortic constriction (TAC)-induced pressure overload, expression of CNOT6L deadenylase subunit was significantly upregulated in the mouse hearts. When CNOT6L gene was genetically deleted, the mice exhibited marked decline of left ventricular contractility and enhancement of fibrosis at 2 weeks after TAC. Transcriptome analyses elucidated that CNOT6L targets tenascin-C mRNA, which stimulates tissue fibrosis and inflammation. CNOT6L deletion markedly upregulated tenascin-C expression in cardiac fibroblasts. Poly(A) tail length and luciferase reporter analyses revealed that CNOT6L catalyzes deadenylation of tenascin-C mRNA likely through interaction with the cis-element in its 3'-untranslated region. Double knockout of tenascin-C and CNOT6L ameliorated cardiac fibrosis and dysfunction in single CNOT6 knockout mice under TAC or chronic infusion of angiotensin II. Thus, CNOT6L deadenylase prevents the progression of heart failure through downregulation of the expression of tenascin-C in cardiac fibroblasts, implicating a potential therapeutic strategy of targeting mRNA deadenylation. SIGNIFICANCE STATEMENT: To our knowledge, this study provides the first evidence that posttranscriptional regulation of tenascin-C expression in cardiac fibroblasts, including cell-type-specific roles of CNOT6L-mediated mRNA deadenylation, is crucial to maintain heart functions against pressure overload stress or angiotensin II-induced hypertension, implicating a potential therapeutic strategy of targeting mRNA deadenylation.