Dataset Information

Pitx2 maintains mitochondrial function during regeneration to prevent myocardial fat deposition.

ABSTRACT: Loss of the paired-like homeodomain transcription factor 2 (Pitx2) in cardiomyocytes predisposes mice to atrial fibrillation and compromises neonatal regenerative capacity. In addition, Pitx2 gain-of-function protects mature cardiomyocytes from ischemic injury and promotes heart repair. Here, we characterized the long-term myocardial phenotype following myocardial infarction (MI) in Pitx2 conditional-knockout (Pitx2 CKO) mice. We found adipose-like tissue in Pitx2 CKO hearts 60?days after MI induced surgically at postnatal day 2 but not at day 8. Molecular and cellular analyses showed the onset of adipogenic signaling in mutant hearts after MI. Lineage tracing experiments showed a non-cardiomyocyte origin of the de novo adipose-like tissue. Interestingly, we found that Pitx2 promotes mitochondrial function through its gene regulatory network, and that the knockdown of a key mitochondrial Pitx2 target gene, Cox7c, also leads to the accumulation of myocardial fat tissue. Single-nuclei RNA-seq revealed that Pitx2-deficient hearts were oxidatively stressed. Our findings reveal a role for Pitx2 in maintaining proper cardiac cellular composition during heart regeneration via the maintenance of proper mitochondrial structure and function.

SUBMITTER: Li L

PROVIDER: S-EPMC6176932 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pitx2 maintains mitochondrial function during regeneration to prevent myocardial fat deposition.

Li Lele L Tao Ge G Hill Matthew C MC Zhang Min M Morikawa Yuka Y Martin James F JF

Development (Cambridge, England) 20180926 18

Loss of the paired-like homeodomain transcription factor 2 (Pitx2) in cardiomyocytes predisposes mice to atrial fibrillation and compromises neonatal regenerative capacity. In addition, Pitx2 gain-of-function protects mature cardiomyocytes from ischemic injury and promotes heart repair. Here, we characterized the long-term myocardial phenotype following myocardial infarction (MI) in Pitx2 conditional-knockout (Pitx2 CKO) mice. We found adipose-like tissue in Pitx2< ...[more]

PMID: 30143541

Similar Datasets

Project description:For patients presenting with a ST-segment elevation myocardial infarction (STEMI), early myocardial reperfusion by primary percutaneous coronary intervention (PPCI) remains the most effective treatment strategy for limiting myocardial infarct size, preserving left ventricular systolic function, and preventing the onset of heart failure. Recent advances in PCI technology to improve myocardial reperfusion and the introduction of novel anti-platelet and anti-thrombotic agents to maintain the patency of the infarct-related coronary artery continue to optimize PPCI procedure. However, despite these improvements, STEMI patients still experience significant major adverse cardiovascular events. One major contributing factor has been the inability to protect the heart against the lethal myocardial reperfusion injury, which accompanies PPCI. Past attempts to translate cardioprotective strategies, discovered in experimental studies to prevent lethal myocardial reperfusion injury, into the clinical setting of PPCI have been disappointing. However, a number of recent proof-of-concept clinical studies suggest that the heart can be 'conditioned' to protect itself against lethal myocardial reperfusion injury, as evidenced by a reduction in myocardial infarct size. This can be achieved using either mechanical (such as ischaemic postconditioning, remote ischaemic preconditioning, therapeutic hypothermia, or hyperoxaemia) or pharmacological (such as cyclosporin-A, natriuretic peptide, exenatide) 'conditioning' strategies as adjuncts to PPCI. Furthermore, recent developments in cardiac magnetic resonance (CMR) imaging can provide a non-invasive imaging strategy for assessing the efficacy of these novel adjunctive therapies to PPCI in terms of key surrogate clinical endpoints such as myocardial infarct size, myocardial salvage, left ventricular ejection fraction, and the presence of microvascular obstruction or intramyocardial haemorrhage. In this article, we review the therapeutic potential of 'conditioning' to protect the heart against lethal myocardial reperfusion injury in STEMI patients undergoing PPCI.

Project description:Obesity is often associated with reduced plasma insulin-like growth factor 1 (IGF-1) levels, oxidative stress, mitochondrial damage, and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high-fat diet-induced oxidative, myocardial, geometric, and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low- (10%) or high-fat (45%) diet to induce obesity. High-fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin 6, insulin, and triglyceride, as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end-systolic and end-diastolic diameter, increased wall thickness, and cardiac hypertrophy in high-fat-fed FVB mice. High-fat diet promoted reactive oxygen species generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca(2+) dysregulation (including depressed peak shortening and maximal velocity of shortening/relengthening), prolonged duration of relengthening, and dampened intracellular Ca(2+) rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor and postreceptor signaling molecules insulin receptor substrate 1 (tyrosine/serine phosphorylation), Akt, glycogen synthase kinase 3?, forkhead transcriptional factors, and mammalian target of rapamycin, as well as downregulated expression of mitochondrial proteins peroxisome proliferator-activated receptor-? coactivator 1? and uncoupling protein 2. Intriguingly, IGF-1 mitigated high-fat-diet feeding-induced alterations in reactive oxygen species, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca(2+) handling, and insulin signaling but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high-fat diet-induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high-fat diet-induced cardiac dysfunction despite persistent cardiac remodeling, possibly because of preserved cell survival, mitochondrial function, and insulin signaling.

Dataset Information

Pitx2 maintains mitochondrial function during regeneration to prevent myocardial fat deposition.

Publications

<i>Pitx2</i> maintains mitochondrial function during regeneration to prevent myocardial fat deposition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets