DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics.

Circulation 2022 Mar 15

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Heart failure is a global public health issue that is associated with increasing morbidity and mortality. Previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure; however, the underlying mechanisms remain unclear. Because kinases have been reported to modulate mitochondrial function, we investigated the effects of DYRK1B (dual-specificity tyrosine-regulated kinase 1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure. We engineered DYRK1B transgenic and knockout mice and used transverse aortic constriction to produce an in vivo model of cardiac hypertrophy. The effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-sequencing analysis and mitochondrial functional analysis. We found that DYRK1B expression was clearly upregulated in failing human myocardium and in hypertrophic murine hearts, as well. Cardiac-specific DYRK1B overexpression resulted in cardiac dysfunction accompanied by a decline in the left ventricular ejection fraction, fraction shortening, and increased cardiac fibrosis. In striking contrast to DYRK1B overexpression, the deletion of DYRK1B mitigated transverse aortic constriction-induced cardiac hypertrophy and heart failure. Mechanistically, DYRK1B was positively associated with impaired mitochondrial bioenergetics by directly binding with STAT3 to increase its phosphorylation and nuclear accumulation, ultimately contributing toward the downregulation of PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α). Furthermore, the inhibition of DYRK1B or STAT3 activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bioenergetics. Taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1B in mitochondrial bioenergetics and the progression of cardiac hypertrophy and heart failure. Consequently, these findings may provide new therapeutic options for patients with heart failure.

Citation

Lingfang Zhuang, Kangni Jia, Chen Chen, Zhigang Li, Jiaxin Zhao, Jian Hu, Hang Zhang, Qin Fan, Chunkai Huang, Hongyang Xie, Lin Lu, Weifeng Shen, Guang Ning, Jiqiu Wang, Ruiyan Zhang, Kang Chen, Xiaoxiang Yan. DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics. Circulation. 2022 Mar 15;145(11):829-846