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Effect of normal and PDK1-deficient human pluripotent stem cells on gene expression during cardiomyocyte differentiation.

ABSTRACT: Cardiac remodeling is the primary factor for the development of ischemic heart failure, which can result from various cardiomyopathies. Pyruvate Dehydrogenase Kinase1 (PDK1) is one of the components of AGC kinase family that maintain mitochondrial metabolism. We here report a PDK1-deficient human cardiac myocyte (CM) model that mimicked the human PDK1 homozygous frameshift mutation and determined the effects of PDK1 dysfunction and its underlying mechanism. PDK1 gene knockout did not affect the pluripotency and differentiation efficiency of hiPSCs. Myocardial cells with a PDK1 gene knockout showed abnormal metabolism, increased oxidative stress levels, decreased cell viability, and increased apoptosis. In addition, lentivirus transfection significantly improved the mitochondrial metabolism in the PDK1-deficient human myocardial model. Taken together, our data provide a PDK1-deficient human cardiomyocyte model that exhibits abnormal mitochondrial metabolism, this model represents an important tool to gain insight into the mechanism of action of metabolism disorders resulting in myocardial remodeling, elucidate the gene-phenotype relationship of PDK1 deficiency, and facilitate drug screening.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289730 | GEO | 2025/02/20

REPOSITORIES: GEO

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Project description:Background Sunitinib is a small molecule tyrosine kinase inhibitor approved for the treatment of diverse cancers. Despite widespread clinical approval the associated cardiovascular toxicity sequelae are of concern; high grade toxicities may lead to dose reduction, interruption or discontinuation. Thus, an effective strategy for the early detection of cardiac damage in the context of sunitinib treatment is warranted. Although yet to be fully elucidated, molecular pathways and kinases implicate include those related to cardiac energy metabolism. We hypothesised that plasticity in cardiac metabolism could represent a novel early marker of cardiotoxicity. Methods and Results Female Balb/CJ mice (n = 36) or Sprague-Dawley rat (n = 12) models were treated with sunitinib. Physiological parameters were measured. An hypothesis driven cardiac positron emission tomography (PET) approach was implemented to investigate alterations in myocardial glucose, fatty acid and oxidative metabolism. Following treatment, blood pressure increased, whilst left ventricular ejection fraction decreased in both models. Increased myocardial glucose uptake after 48 hours indicated early perturbations in glucose metabolism. Myocardial fatty acid metabolism appeared increased as a result of sunitinib treatment indicated by PET but electron microscopy revealed significantly increased storage of lipids in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top cardiac signalling pathways perturbed by sunitinib treatment. [11C]Acetate-PET data suggested a decrease in myocardial perfusion following 5 days of treatment. Conclusions Data implicates sunitinib as a mediator of compromised myocardial energy metabolism. Increased reliance on glycolysis, increases in myocardial lipid deposition and perturbed mitochondrial function may ultimately result in a fundamental energy crisis manifesting as compromised cardiac function, the long term effects of which are unknown. Our data support the utility of an hypothesis driven PET approach to monitor cardiac metabolic pathway remodelling in response to sunitinib, which may ultimately have clinical utility as a novel safety imaging biomarker strategy.

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Effect of normal and PDK1-deficient human pluripotent stem cells on gene expression during cardiomyocyte differentiation.

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