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

Abstract

Background: 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. Since kinases have been reported to modulate mitochondrial function, we investigated the effects of dual-specificity tyrosine-regulated kinase 1B (DYRK1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure. Methods: We engineered DYRK1B transgenic and knock out mice and used transverse aortic constriction (TAC) to produce an in vivo model of cardiac hypertrophy. The effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-seq analysis and mitochondrial functional analysis. Results: We found that DYRK1B expression was clearly upregulated in failing human myocardium as well as in hypertrophic murine hearts. 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 TAC-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. Furthermore, the inhibition of DYRK1B or STAT3 activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bioenergetics. Conclusions: 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.

Beneficial Effects of O-GlcNAc Stimulation in a Young Rat Model of Sepsis: Beyond Modulation of Gene Expression

“…Reinforcing this observation, genes involved in the MAPK, mTOR, TLR2/MyD88 and JAK/STAT pathway are also up-regulated in the LPS group, as recently described in sepsis patients [ 26 ], confirming the pertinence of such approaches. JAK/STAT3 is a major pathway described as cardio-protective [ 27 , 28 ]; however, this pathway could also contribute to cardiac dysfunction [ 29 , 30 , 31 ], notably during septic shock [ 32 , 33 ]. Recent studies provide some evidence of therapeutic potential for targeting STAT3 in the cecal and ligature-puncture-induced sepsis model [ 34 , 35 ].…”

Dual-Specificity Phosphatase 19 Alleviates Cardiac Hypertrophy Via Inhibiting ASK1 Phosphorylation

“…Various important pathological changes (such as myocardial hypertrophy and interstitial brosis) are participated in the progression of myocardial remodeling induced by pressure overload [17]. There is an interaction between myocardial hypertrophy and interstitial brosis during the development of myocardial remodeling [18].…”

Long non-coding RNA KCND1 protects hearts from hypertrophy by targeting YBX1

“…Knowing that cardiac mitochondrial impairment can lead to cardiac hypertrophy [16] ; thus, we determined the cardiac mitochondrial integrity and function after silencing LncKCND1 through JC-1 staining, and quantified ROS and ATP production. As shown in Figure 2E, silencing of LncKCND1 significantly reduced ATP production.…”