File Download
Supplementary

postgraduate thesis: Decoding the role of FOXO1 in diabetic cardiomyopathy in type 1 diabetic rats

TitleDecoding the role of FOXO1 in diabetic cardiomyopathy in type 1 diabetic rats
Authors
Advisors
Advisor(s):Xia, ZXu, A
Issue Date2019
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Yan, D. [严丹]. (2019). Decoding the role of FOXO1 in diabetic cardiomyopathy in type 1 diabetic rats. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
AbstractDiabetic cardiomyopathy (DCM) is a multifactorial disease and among which, altered cardiac metabolism plays a major role in the progression of DCM. In diabetes, diminished glucose oxidation (GO) in diabetic hearts is partially attributable to declined insulin signal and thus imposes heart more reliable on fatty acid β oxidation for energy supply. The resulted imbalanced oxidative metabolism in diabetic myocardium, manifested by increased fatty acid oxidation (FAO) and decreased GO, is proposed to be an underlying cause of mitochondrial dysfunction and often associated with cardiac dysfunction. Forkhead box protein O1 (FOXO1) is a member of “O” subgroup of Forkhead box family of transcriptional factors. AKT-induced FOXO1 phosphorylation promotes FOXO1 nuclear extrusion and active termination. Interestingly, in obesity-induced diabetic mice, cardiac deletion of FOXO1 reduced cardiac lipid uptake and lipid accumulation, thus alleviating cardiac dysfunction. Recently, activation of FOXO1 has been demonstrated to reduce GO by stimulating pyruvate dehydrogenase kinase 4 (PDK4) expression and subsequently inactivating pyruvate dehydrogenase (PDH) in mice heart. Under the context that FOXO1 over-activation is present in hearts of diabetic animals, it is reasonable to postulate that FOXO1 activation contribute to the imbalanced oxidative metabolism in diabetic hearts. Here, I studied the role of FOXO1 activation in the disarranged cardiac metabolism and its action on mitochondrial dysfunction as well as reduced cardiac performance in diabetic rats. In my study, I found that streptozocin (STZ)-induced diabetic rat hearts displayed deminished AKT phosphorylation levels and increased FOXO1 activation, concomitant with over-expressed PDK4 and carnitine palmitoyltransferase I (CPT1), which were accompanied with elevated FAO and decreased GO in diabetic cardiomyocytes, as well as mitochondrial dysfunction and reduced cardiac performance. However, supplementation with 50mg/kg AS1842856 (a FOXO1 specific inhibitor) for one week significantly reduced cardiac nuclear presence of FOXO1, PDK4 expression and CPT1 expression, and meanwhile improved mitochondrial function and cardiac performance. Moreover, diabetic cardiomyocytes treated with 1mM AS1842856 showed normalized GO and FAO. To summarize, I demonstrated that FOXO1 activation, through stimulating PDK4 and CPT1 expression, induced the shift of substrate selection from GO to FAO and subsequently conducted adverse effects on mitochondrial function, contributing to cardiac dysfunction and exacerbated DCM. Furthermore, I evidenced that AS1842856 is a promising drug candidate to confer cardioprotection against DCM though normalizing the imbalanced cardiac oxidative metabolism.
DegreeDoctor of Philosophy
SubjectForkhead transcription factors
Cardiovascular system - Diseases
Diabetic angiopathies
Dept/ProgramAnaesthesiology
Persistent Identifierhttp://hdl.handle.net/10722/273777

 

DC FieldValueLanguage
dc.contributor.advisorXia, Z-
dc.contributor.advisorXu, A-
dc.contributor.authorYan, Dan-
dc.contributor.author严丹-
dc.date.accessioned2019-08-14T03:29:52Z-
dc.date.available2019-08-14T03:29:52Z-
dc.date.issued2019-
dc.identifier.citationYan, D. [严丹]. (2019). Decoding the role of FOXO1 in diabetic cardiomyopathy in type 1 diabetic rats. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/273777-
dc.description.abstractDiabetic cardiomyopathy (DCM) is a multifactorial disease and among which, altered cardiac metabolism plays a major role in the progression of DCM. In diabetes, diminished glucose oxidation (GO) in diabetic hearts is partially attributable to declined insulin signal and thus imposes heart more reliable on fatty acid β oxidation for energy supply. The resulted imbalanced oxidative metabolism in diabetic myocardium, manifested by increased fatty acid oxidation (FAO) and decreased GO, is proposed to be an underlying cause of mitochondrial dysfunction and often associated with cardiac dysfunction. Forkhead box protein O1 (FOXO1) is a member of “O” subgroup of Forkhead box family of transcriptional factors. AKT-induced FOXO1 phosphorylation promotes FOXO1 nuclear extrusion and active termination. Interestingly, in obesity-induced diabetic mice, cardiac deletion of FOXO1 reduced cardiac lipid uptake and lipid accumulation, thus alleviating cardiac dysfunction. Recently, activation of FOXO1 has been demonstrated to reduce GO by stimulating pyruvate dehydrogenase kinase 4 (PDK4) expression and subsequently inactivating pyruvate dehydrogenase (PDH) in mice heart. Under the context that FOXO1 over-activation is present in hearts of diabetic animals, it is reasonable to postulate that FOXO1 activation contribute to the imbalanced oxidative metabolism in diabetic hearts. Here, I studied the role of FOXO1 activation in the disarranged cardiac metabolism and its action on mitochondrial dysfunction as well as reduced cardiac performance in diabetic rats. In my study, I found that streptozocin (STZ)-induced diabetic rat hearts displayed deminished AKT phosphorylation levels and increased FOXO1 activation, concomitant with over-expressed PDK4 and carnitine palmitoyltransferase I (CPT1), which were accompanied with elevated FAO and decreased GO in diabetic cardiomyocytes, as well as mitochondrial dysfunction and reduced cardiac performance. However, supplementation with 50mg/kg AS1842856 (a FOXO1 specific inhibitor) for one week significantly reduced cardiac nuclear presence of FOXO1, PDK4 expression and CPT1 expression, and meanwhile improved mitochondrial function and cardiac performance. Moreover, diabetic cardiomyocytes treated with 1mM AS1842856 showed normalized GO and FAO. To summarize, I demonstrated that FOXO1 activation, through stimulating PDK4 and CPT1 expression, induced the shift of substrate selection from GO to FAO and subsequently conducted adverse effects on mitochondrial function, contributing to cardiac dysfunction and exacerbated DCM. Furthermore, I evidenced that AS1842856 is a promising drug candidate to confer cardioprotection against DCM though normalizing the imbalanced cardiac oxidative metabolism. -
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshForkhead transcription factors-
dc.subject.lcshCardiovascular system - Diseases-
dc.subject.lcshDiabetic angiopathies-
dc.titleDecoding the role of FOXO1 in diabetic cardiomyopathy in type 1 diabetic rats-
dc.typePG_Thesis-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineAnaesthesiology-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2019-
dc.identifier.mmsid991044128171903414-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats