| First Author | Young A | Year | 2022 |
| Journal | Circ Res | Volume | 130 |
| Issue | 9 | Pages | 1345-1361 |
| PubMed ID | 35369706 | Mgi Jnum | J:362548 |
| Mgi Id | MGI:8158972 | Doi | 10.1161/CIRCRESAHA.121.320005 |
| Citation | Young A, et al. (2022) Inhibition of DYRK1a Enhances Cardiomyocyte Cycling After Myocardial Infarction. Circ Res 130(9):1345-1361 |
| abstractText | BACKGROUND: DYRK1a (dual-specificity tyrosine phosphorylation-regulated kinase 1a) contributes to the control of cycling cells, including cardiomyocytes. However, the effects of inhibition of DYRK1a on cardiac function and cycling cardiomyocytes after myocardial infarction (MI) remain unknown. METHODS: We investigated the impacts of pharmacological inhibition and conditional genetic ablation of DYRK1a on endogenous cardiomyocyte cycling and left ventricular systolic function in ischemia-reperfusion (I/R) MI using alphaMHC-MerDreMer-Ki67p-RoxedCre::Rox-Lox-tdTomato-eGFP (RLTG) (denoted alphaDKRC::RLTG) and alphaMHC-Cre::Fucci2aR::DYRK1a(flox/flox) mice. RESULTS: We observed that harmine, an inhibitor of DYRK1a, improved left ventricular ejection fraction (39.5+/-1.6% and 29.1+/-1.6%, harmine versus placebo, respectively), 2 weeks after I/R MI. Harmine also increased cardiomyocyte cycling after I/R MI in alphaDKRC::RLTG mice, 10.8+/-1.5 versus 24.3+/-2.6 enhanced Green Fluorescent Protein (eGFP)+ cardiomyocytes, placebo versus harmine, respectively, P=1.0x10(-)(3). The effects of harmine on left ventricular ejection fraction were attenuated in alphaDKRC::DTA mice that expressed an inducible diphtheria toxin in adult cycling cardiomyocytes. The conditional cardiomyocyte-specific genetic ablation of DYRK1a in alphaMHC-Cre::Fucci2aR::DYRK1a(flox/flox) (denoted DYRK1a k/o) mice caused cardiomyocyte hyperplasia at baseline (210+/-28 versus 126+/-5 cardiomyocytes per 40x field, DYRK1a k/o versus controls, respectively, P=1.7x10(-)(2)) without changes in cardiac function compared with controls, or compensatory changes in the expression of other DYRK isoforms. After I/R MI, DYRK1a k/o mice had improved left ventricular function (left ventricular ejection fraction 41.8+/-2.2% and 26.4+/-0.8%, DYRK1a k/o versus control, respectively, P=3.7x10(-2)). RNAseq of cardiomyocytes isolated from alphaMHC-Cre::Fucci2aR::DYRK1a(flox/flox) and alphaMHC-Cre::Fucci2aR mice after I/R MI or Sham surgeries identified enrichment in mitotic cell cycle genes in alphaMHC-Cre::Fucci2aR::DYRK1a(flox/flox) compared with alphaMHC-Cre::Fucci2aR. CONCLUSIONS: The pharmacological inhibition or cardiomyocyte-specific ablation of DYRK1a caused baseline hyperplasia and improved cardiac function after I/R MI, with an increase in cell cycle gene expression, suggesting the inhibition of DYRK1a may serve as a therapeutic target to treat MI. |
