Journal
CARDIOVASCULAR RESEARCH
Volume 97, Issue 3, Pages 393-403Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvs426
Keywords
FoxO1; Heart; Metabolism; Cell death; Diabetes
Categories
Funding
- Heart and Stroke Foundation of BC
- Heart and Stroke Foundation of Yukon
- Canadian Diabetes Association
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Diabetic cardiomyopathy is a term used to describe cardiac muscle damage-induced heart failure. Multiple structural and biochemical reasons have been suggested to induce this disorder. The most prominent feature of the diabetic myocardium is attenuated insulin signalling that reduces survival kinases (Akt), potentially switching on protein targets like FoxOs, initiators of cell death. FoxO1, a prominent member of the forkhead box family and subfamily O of transcription factors and produced from the FKHR gene, is involved in regulating metabolism, cell proliferation, oxidative stress response, immune homeostasis, pluripotency in embryonic stem cells, and cell death. In this review we describe distinctive functions of FoxOs, specifically FoxO1 under conditions of nutrient excess, insulin resistance and diabetes, and its manipulation to restore metabolic equilibrium to limit cardiac damage due to cell death. Because FoxO1 helps cardiac tissue to combat a variety of stress stimuli, it could be a major determinant in regulating diabetic cardiomyopathy. In this regard, we highlight studies from our group and others who illustrate how cardiac tissue-specific FoxO1 deletion protects the heart against cardiomyopathy and how its down-regulation in endothelial tissue could prevent against atherosclerotic plaques. In addition, we also describe studies that show FoxO1s beneficial qualities by highlighting their role in inducing anti-oxidant, autophagic, and anti-apoptotic genes under stress conditions of ischaemiareperfusion and myocardial infarction. Thus, the aforementioned FoxO1 traits could be useful in curbing cardiac tissue-specific impairment of function following diabetes.
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