2. Academic Validation
  3. GSK-3 at the heart of cardiometabolic diseases: Isoform-specific targeting is critical to therapeutic benefit

GSK-3 at the heart of cardiometabolic diseases: Isoform-specific targeting is critical to therapeutic benefit

  • Biochim Biophys Acta Mol Basis Dis. 2023 Aug;1869(6):166724. doi: 10.1016/j.bbadis.2023.166724.
Prachi Umbarkar 1,  Sulivette Y Ruiz Ramirez 2,  Angelica Toro Cora 3,  Sultan Tousif 4,  Hind Lal 5
Affiliations

Affiliations

  • 1 Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: [email protected].
  • 2 Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: [email protected].
  • 3 Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: [email protected].
  • 4 Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: [email protected].
  • 5 Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: [email protected].
PMID: 37094727 DOI: 10.1016/j.bbadis.2023.166724
Abstract

Glycogen synthase kinase-3 (GSK-3) is a family of serine/threonine kinases. The GSK-3 family has 2 isoforms, GSK-3α and GSK-3β. The GSK-3 isoforms have been shown to play overlapping as well as isoform-specific-unique roles in both, organ homeostasis and the pathogenesis of multiple diseases. In the present review, we will particularly focus on expanding the isoform-specific role of GSK-3 in the pathophysiology of cardiometabolic disorders. We will highlight recent data from our lab that demonstrated the critical role of cardiac fibroblast (CF) GSK-3α in promoting injury-induced myofibroblast transformation, adverse fibrotic remodeling, and deterioration of cardiac function. We will also discuss studies that found the exact opposite role of CF-GSK-3β in cardiac fibrosis. We will review emerging studies with inducible cardiomyocyte (CM)-specific as well as global isoform-specific GSK-3 KOs that demonstrated inhibition of both GSK-3 isoforms provides benefits against obesity-associated cardiometabolic pathologies. The underlying molecular interactions and crosstalk among GSK-3 and Other signaling pathways will be discussed. We will briefly review the specificity and limitations of the available small molecule inhibitors targeting GSK-3 and their potential applications to treat metabolic disorders. Finally, we will summarize these findings and offer our perspective on envisioning GSK-3 as a therapeutic target for the management of cardiometabolic diseases.

Keywords

Cardiometabolic disease; Fibrosis; Glycogen synthase kinase; Heart failure; Hypertrophy; Myocardial infarction; Obesity.

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