Double face of glycolytic enzyme ENO1 in heart failure
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RATIONALE
Glycolytic enzyme ENO1 is dysregulated in both nucleus and cytoplasm in failing hearts.
OBJECTIVE
We aim to elucidate the function and mechanism of nuclear and cytoplasmic ENO1 in pressure-overload induced heart failure.
METHODS AND RESULTS
Subcellular fractionation followed by western blotting revealed increase of nuclear and cytoplasmic localized ENO1, a glycolysis enzyme, in transverse aortic constriction (TAC)-induced failing hearts. In vivo study showed that overexpression of nuclear ENO1 exacerbated heart failure while cytoplasmic ENO1 exerted an opposite effect. Mechanistically, cytoplasmic ENO1 activated AKT phosphorylation and increased the contractility of cardiomyocytes. In nucleus, ENO1 bound to NOC2L, a transcriptional repressor, to decrease NOC2L recruitment on glycoprotein nonmetastatic melanoma protein B (GPNMB) promoter, leading to GPNMB transcriptional activation as revealed by immunoprecipitation coupled with mass-spectrometry, cut-tag sequencing and chromatin immunoprecipitation polymerase chain reaction (ChIP-PCR). Furthermore, co-culture assays showed that GPNMB secreted by cardiomyocytes activated cardiac fibroblasts differentiation, leading to augmented pathological cardiac remodeling involving both cardiac hypertrophy and fibrosis through a cardiomyocytes-fibroblast crosstalk.
CONCLUSIONS
We uncovered the protective role of cytoplasmic ENO1 and detrimental role of nuclear ENO1 in cardiac pathological remodeling. Inhibition of cardiac nuclear ENO1-GPNMB pathway by rAAV-tnt-shRNA provide new insights for treating heart failure.
