Inhibition of DYRK1a Enhances Cardiomyocyte Cycling After Myocardial Infarction

Alexander Young; Leigh A Bradley; Elizabeth Farrar; Helen O Bilcheck; Svyatoslav Tkachenko; Jeffrey J Saucerman; Stefan Bekiranov; Matthew J Wolf

doi:10.1161/CIRCRESAHA.121.320005

Inhibition of DYRK1a Enhances Cardiomyocyte Cycling After Myocardial Infarction

Circ Res. 2022 Apr 29;130(9):1345-1361. doi: 10.1161/CIRCRESAHA.121.320005. Epub 2022 Apr 4.

Authors

Alexander Young^{1

2}, Leigh A Bradley^{1

2}, Elizabeth Farrar¹, Helen O Bilcheck^{1

2}, Svyatoslav Tkachenko³, Jeffrey J Saucerman³, Stefan Bekiranov⁴, Matthew J Wolf^{1

2}

Affiliations

¹ Department of Medicine (A.Y., L.A.B., E.F., H.O.B., M.J.W.), University of Virginia, Charlottesville.
² Robert M. Berne Cardiovascular Research Center (A.Y., L.A.B., H.O.B., M.J.W.), University of Virginia, Charlottesville.
³ Departments of Biomedical Engineering (S.T., J.J.S.), University of Virginia, Charlottesville.
⁴ Biochemistry and Molecular Genetics (S.B.), University of Virginia, Charlottesville.

Abstract

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 αMHC-MerDreMer-Ki67p-RoxedCre::Rox-Lox-tdTomato-eGFP (RLTG) (denoted αDKRC::RLTG) and αMHC-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 αDKRC::RLTG mice, 10.8±1.5 versus 24.3±2.6 enhanced Green Fluorescent Protein (eGFP)+ cardiomyocytes, placebo versus harmine, respectively, P=1.0×10^-³. The effects of harmine on left ventricular ejection fraction were attenuated in αDKRC::DTA mice that expressed an inducible diphtheria toxin in adult cycling cardiomyocytes. The conditional cardiomyocyte-specific genetic ablation of DYRK1a in αMHC-Cre::Fucci2aR::DYRK1a^flox/flox (denoted DYRK1a k/o) mice caused cardiomyocyte hyperplasia at baseline (210±28 versus 126±5 cardiomyocytes per 40× field, DYRK1a k/o versus controls, respectively, P=1.7×10^-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=3.7×10^-2). RNAseq of cardiomyocytes isolated from αMHC-Cre::Fucci2aR::DYRK1a^flox/flox and αMHC-Cre::Fucci2aR mice after I/R MI or Sham surgeries identified enrichment in mitotic cell cycle genes in αMHC-Cre::Fucci2aR::DYRK1a^flox/flox compared with αMHC-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.

Keywords: harmine; hyperplasia; myocardial infarction; phosphorylation; tyrosine.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Harmine / metabolism
Harmine / pharmacology
Hyperplasia / metabolism
Mice
Myocardial Infarction* / metabolism
Myocytes, Cardiac* / metabolism
Stroke Volume
Ventricular Function, Left

Substances

Harmine

Abstract

Publication types

MeSH terms

Substances

Grants and funding