In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. Suppl_3 ( 2020-11-17)
Abstract:
Introduction: Cardiomyopathy in type 1 diabetes (T1D) is accompanied by impaired mitochondrial function, oxidative stress and lipotoxicity. We showed that cardiomyocyte (CM) Krüppel-like factor 5 (KLF5) is increased in streptozotocin-induced T1D and induces Peroxisome Proliferator Activated Receptor (PPAR)α in mice. Hypothesis: KLF5 upregulation by FOXO1 induces diabetic cardiomyopathy (DbCM). Methods and Results: Analyses in CM from diabetic patients showed higher KLF5 mRNA levels compared to non-diabetic individuals. In vitro mechanistic and in vivo analyses in αMHC- Foxo1 -/- mice revealed that FOXO1 stimulates KLF5 expression via direct promoter binding. Genetic inhibition of CM FOXO1 alleviated DbCM. Additionally, AAV-mediated CM-specific KLF5 overexpression in C57Bl/6 (WT) mice induced cardiac dysfunction. Mice with CM-specific KLF5 constitutive expression (αMHC-rtTA- Klf5 ), which we generated, recapitulated cardiomyopathy without T1D. Moreover, Pparα -/- mice with T1D, had higher CM-KLF5 levels and developed DbCM, suggesting that KLF5-driven DbCM is PPARα-independent. Additionally, CM-KLF5 induced oxidative stress through increased NADPH oxidase (NOX)4 expression and lower mitochondria abundance. Conversely, KLF5 inhibition prevented NOX4 upregulation and superoxide formation. Furthermore, CM-KLF5 promoted NOX4 expression via direct promoter binding. Antioxidant treatment in diabetic WT and αMHC-rtTA- Klf5 mice alleviated cardiac dysfunction partially, suggesting other pathways that contribute in KLF5-induced DbCM. For that, we performed cardiac lipidome analysis where we found clustering of αMHC-rtTA- Klf5 with diabetic WT mice. Of note, KLF5 inhibition in diabetic mice resulted in similar lipidome with non-diabetic WT mice. Individual lipid species analysis showed increased ceramide accumulation in diabetic WT and αMHC-rtTA- Klf5 mice that was reversed upon KLF5 inhibition. Thus, CM-KLF5 activation correlates with cardiac ceramide accumulation, that has been associated with cardiac lipotoxicity. Conclusions: In conclusion, T1D stimulates FOXO1, which induces CM-KLF5 expression that leads to oxidative stress and DbCM in a non-PPARα-dependent manner, as well as to cardiac ceramide accumulation.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.142.suppl_3.16563
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2020
detail.hit.zdb_id:
1466401-X
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