Biology subjects

Heather, L. C.

Publications and source records attributed to Heather, L. C..

3 recordsLinked to original sources

bioRxiv2024

Multiomics-based assessment of 2D and 3D human iPSC-cardiomyocyte models of insulin resistance demonstrate metabolic and contractile dysfunction that recapitulates diabetic cardiomyopathy.

In type II diabetes (T2DM), the heart is exposed to hyperglycaemia, hyperlipidaemia, and hyperinsulinaemia, leading to insulin resistance and metabolic dysfunction, culminating in diabetic cardiomyopathy (DbCM). Human-centric models of DbCM are needed to provide mechanistic insights and therapeutic targets in a translationally relevant setting. We hypothesised that culturing human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in an "insulin resistance" (IR) media, and assessing this using a systems biology approach, would offer a comprehensive evaluation of dysregulated pathways, establishing their suitability as a model of DbCM. Culturing hiPSC-CMs in 2D or 3D as engineered heart tissue (EHT) in IR media induced insulin resistance and activated numerous pathways implicated in DbCM, including metabolic remodelling, mitochondrial dysfunction, extracellular matrix remodelling, and endoplasmic reticulum stress. Pathways involved in fatty acid oxidation were upregulated, while those involved in glucose metabolism were downregulated, which was validated using radioisotope flux measurements. Adaptation to hypoxia, a key component of post-ischaemic remodelling, was blunted in the 2D IR hiPSC-CMs. Combining proteomic and transcriptomic analyses in the IR 3D EHT revealed significant enrichment of DbCM pathways, with subnetworks enriched for several metabolic and diabetes-related pathways. Additionally, IR 3D EHT displayed impaired relaxation, mimicking the diastolic dysfunction observed in T2DM patients. In conclusion, culturing hiPSC-CM in 2D or 3D in an IR media activates multiple mechanisms implicated in the development of DbCM, with IR 3D EHT also recapitulating the diastolic dysfunction present in patients with T2DM.

molecular biology↗

bioRxiv2022

AICAR prevents doxorubicin-induced heart failure in rats by ameliorating cardiac atrophy and improving fatty acid oxidation

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to functional cardiac decline and ultimately, congestive heart failure (HF). Impaired mitochondrial function and energetics are thought to be key factors driving progression into HF. We have previously shown in a rat model of chronic intravenous DOX-administration that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and oxidative metabolism, including fatty acid oxidation. We hypothesized that AMPK activation could restore mitochondrial number and function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. We therefore set out to assess whether 5-aminoimidazole-4-carboxamide 1-{beta}-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this clinically relevant rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. We show that this could be due to normalisation of substrate supply to the heart, as AICAR prevented DOX-induced dyslipidaemia. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, despite no increase in mitochondrial number. In addition, we found that AICAR prevented excessive myocardial atrophy, and RNAseq analysis showed that this may be due to normalisation of protein synthesis pathways, which are impaired in DOX-treated rat hearts. Taken together, these results show promise for use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac mass and improve cardiac function.

biochemistry↗

bioRxiv2018

Assessing the effect of hypoxia on cardiac metabolism using hyperpolarized 13C magnetic resonance spectroscopy

Abstract summaryHypoxia plays a role in many diseases and can have a wide range of effects on cardiac metabolism depending on the extent of the hypoxic insult. Non-invasive imaging methods could shed valuable light on the metabolic effects of hypoxia on the heart in vivo. Hyperpolarized carbon-13 magnetic resonance spectroscopy (HP 13C MRS) in particular is an exciting technique for imaging metabolism that could provide such information.\n\nThe aim of our work was, therefore, to establish whether hyperpolarized 13C MRS can be used to assess the in vivo response of cardiac metabolism to systemic acute and chronic hypoxic exposure. Groups of healthy male Wistar rats were exposed to either acute (30 minutes), one week or three weeks of hypoxia. In vivo MRS of hyperpolarized [1-13C]pyruvate was carried out along with assessments of physiological parameters and ejection fraction. No significant changes in heart rate, respiration rate, or ejection fraction were observed at any timepoint. Haematocrit was elevated after one week and three weeks of hypoxia.\n\nThirty minutes of hypoxia resulted in a significant reduction in pyruvate dehydrogenase (PDH) flux, whereas one or three weeks of hypoxia resulted in a PDH flux that was not different to normoxic animals. Conversion of hyperpolarized [1-13C]pyruvate into [1-13C]lactate was elevated following acute hypoxia, suggestive of enhanced anaerobic glycolysis. Elevated HP pyruvate to lactate conversion was also seen at the one-week timepoint, in concert with an increase in lactate dehydrogenase (LDH) expression. Following three weeks of hypoxic exposure, cardiac metabolism was comparable to that observed in normoxia.\n\nWe have successfully visualized of the effects of systemic hypoxia on cardiac metabolism using hyperpolarized 13C MRS, with differences observed following 30 minutes and 1 week of hypoxia. This demonstrates the potential of in vivo hyperpolarized 13C MRS data for assessing the cardiometabolic effects of hypoxia in disease.

physiology↗