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Review
. 2016 Mar 8:15:44.
doi: 10.1186/s12933-016-0361-1.

Forkhead box transcription factor 1: role in the pathogenesis of diabetic cardiomyopathy

Vidya Kandula  1 , Ramoji Kosuru  2 , Haobo Li  3 , Dan Yan  4 , Qiqi Zhu  5   6 , Qingquan Lian  7 , Ren-Shan Ge  8 , Zhengyuan Xia  9   10 , Michael G Irwin  11
Affiliations
Review

Forkhead box transcription factor 1: role in the pathogenesis of diabetic cardiomyopathy

Vidya Kandula et al. Cardiovasc Diabetol. .

Abstract

Diabetic cardiomyopathy (DCM) is a disorder of the heart muscle in people with diabetes that can occur independent of hypertension or vascular disease. The underlying mechanism of DCM is incompletely understood. Some transcription factors have been suggested to regulate the gene program intricate in the pathogenesis of diabetes prompted cardiac injury. Forkhead box transcription factor 1 is a pleiotropic transcription factor that plays a pivotal role in a variety of physiological processes. Altered FOXO1 expression and function have been associated with cardiovascular diseases, and the important role of FOXO1 in DCM has begun to attract attention. In this review, we focus on the FOXO1 pathway and its role in various processes that have been related to DCM, such as metabolism, oxidative stress, endothelial dysfunction, inflammation and apoptosis.

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Figures

Fig. 1
Fig. 1
Regulation and function of FOXO-1 in the development of DCM. In diabetes mellitus, various stimuli like excess glucose, excess lipids, oxygen free radicals, cytokines and other growth factors triggers several mechanisms that promote posttranslational modifications like phosphorylation, acetylation, deacetylation which may regulate the FOXO-1 activity and function. Akt promotes the phosphorylation and translocation of FOXO1 to cytosol and facilitates its binding with 14-3-3 protein which directs it for degradation whereas protein phosphatase 2A (PP2A) causes dephosphorylation and translocates FOXO1 to nucleus from cytosol. E3 ubiquitin ligase facilitates ubiquination of FOXO1, while ubiquitin specific protease (USP7) inverted the process. Further, phosphorylation by Mst1 stimulates FOXO1 transcriptional activity. In addition, cAMP response element binding protein (CBP) and p300 histone acetyltransferase acetylates FOXO1, and silent information regulator 1 (SIRT1) deacetylates it. Activated FOXO-1 binds to the FOXO-binding site and triggers several genes involved in inflammation, oxidative stress, nitrosative stress, glucose and lipid metabolism, hypertrophy, autophagy and apoptosis that finally leads to alteration of cardiac structure, metabolism, function and cardiac cell death. P phoshorylation; Ub ubiquitination; Ac acetylation
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