Cardiac KLF5 Is Upregulated by FOXO1 and Accounts for Cardiomyopathy in Type 1 Diabetes
Authors: Kyriazis Ioannis , Hoffman Matthew , Kalliora Charikleia , Gaignebet Lea , Bannister Thomas D , Christofidou‐Solomidou Melpo , Goldberg Ira J , Yang Vincent W , Bialkowska Agnieszka B , Kararigas Georgios , Drosatos Konstantinos 
Published: June 2021

Diabetic cardiomyopathy (DCM) is defined as myocardial dysfunction in the absence of hypertension and coronary artery disease. We found that the transcription factor Krüppel‐like factor (KLF)5 drives cardiac fatty acid oxidation, as well as that genetic and pharmacologic inhibition protects diabetic mice from heart failure. Previously, we showed that cardiomyocyte (CM) KLF5 is a novel regulator of fatty acid metabolism and its expression is decreased at the early stage of type 1 diabetes (T1D) and increased later in streptozotocin‐induced T1D mouse model. Here, we assessed how KLF5 affects cardiac metabolism and function.

Isolated CMs obtained from patients with aortic stenosis showed higher (3‐fold) KLF5 mRNA levels in individuals with diabetes. Assessment of fuel dependence (Seahorse analysis) in primary CMs from T1D mice showed that CM metabolism varies depending on the length of T1D. At the early stage (4 weeks), cardiac KLF5 is downregulated and CMs primarily utilize glucose; later in the course of T1D (12 weeks), KLF5 is upregulated and CMs depend more on fatty acid catabolism. In silico analysis of the Klf5 promoter followed by in vitro and in vivo gain and loss of function experiments, as well as chromatin immunoprecipitation, showed that nuclear retention of FOXO1 upon insulin signaling inhibition and transcriptional activation via deacetylation, increases KLF5 expression at the late T1D stage by direct binding on Klf5 promoter. Deletion of CM FOXO1 (αMHC‐Foxo1−/− mice) prevented KLF5 upregulation and rescued cardiac function during T1D. Similarly, induction of T1D in either αMHC‐Klf5−/− or C57BL/6 mice treated with pharmacological KLF5 inhibitor (ML264) did not cause cardiac dysfunction at late T1D stage.

We confirmed involvement of KLF5 in DCM by observing cardiac dysfunction both in inducible CM‐specific KLF5 overexpression (αMHC‐rtTA‐Klf5) that we generated, and C57Bl/6 mice injected with AAV9 that expresses KLF5 under the CM‐specific cTnT promoter. The αMHC‐rtTA‐Klf5 mice had increased cardiac superoxide levels, which are associated with DCM. Conversely, superoxide levels were diminished in both αMHC‐Klf5−/− and ML264‐treated C57BL/6 mice at late T1D stage. Also, treatment of aMHC‐rtTA‐Klf5 mice with the antioxidant LGM2605 reduced superoxide levels and restored cardiac function. Finally, KLF5 overexpression in AC16 cells increased mitochondrial calcium uptake and superoxide formation.

Conclusively, KLF5 expression is induced by FOXO1 activation in late T1D and causes DCM via oxidative stress.

Support or Funding Information

Study supported by National Heart, Lung and Blood Institute (NHLBI) R01HL130218 and WW Smith Foundation (K.D). I.D.K. 18POST34060150 AHA and the Kahn Family Post‐Doctoral Fellowship. M.H. 18PRE34060115 AHA pre‐doctoral fellowship.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.