Insulin Receptors and Insulin Action in the Heart: The Effects of Left Ventricular Assist Devices

Pantazi, Konstantina; Karlafti, Eleni; Bekiaridou, Αlexandra; Didagelos, Matthaios; Ziakas, Antonios; Didangelos, Triantafyllos

doi:10.3390/biom12040578

Cited by 7 publications

(3 citation statements)

References 69 publications

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“…Considering the elevation of titin stiffness in both mouse and human models of HCM [93], our results suggest that the repercussions of higher titin stiffness could be more severe in HCM patients compared to HCM mouse models. Growth factors activate the PI3K/AKT pathway via IRS1, promoting physiological growth, survival, and glucose uptake and utilization in cardiomyocytes [94,95]. Thus, the predicted increase in IRS1 activation by growth factor receptors in HCM patients compared to HCM mouse models, especially MyHC mutants, could indicate an elevated compensatory response in HCM patients through higher physiological hypertrophy, cell survival, and glucose metabolism.…”

Section: Heterogeneity In Hcmmentioning

confidence: 99%

Modeling Cardiomyocyte Signaling and Metabolism Predicts Genotype to Phenotype Mechanisms in Hypertrophic Cardiomyopathy

Khalilimeybodi,

Saucerman,

Rangamani

2023

Preprint

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Familial hypertrophic cardiomyopathy (HCM) is a significant precursor of heart failure and sudden cardiac death, primarily caused by mutations in sarcomeric and structural proteins. Despite the extensive research on the HCM genotype, the complex, context-specific nature of many signaling and metabolic pathways linking the HCM genotype to phenotype has hindered therapeutic advancements for patients. To address these challenges, here, we have developed a computational systems biology model of HCM at the cardiomyocyte level. Utilizing a stochastic logic-based ODE method, we integrate subcellular systems in cardiomyocytes that jointly modulate HCM genotype to phenotype, including cardiac signaling, metabolic, and gene regulatory networks, as well as posttranslational modifications linking these networks. After validating with experimental data on changes in activity of signaling species in HCM context and transcriptomes of two HCM mouse models (R403Q-αMyHC and R92W-TnT), the model predicts significant changes in cardiomyocyte metabolic functions such as ATP synthase deficiency and a transition from fatty acids to carbohydrate metabolism in HCM. The model indicated major shifts in glutamine-related metabolism and increased apoptosis after HCM-induced ATP synthase deficiency. Aligned with prior experimental studies, we predicted that the transcription factors STAT, SRF, GATA4, TP53, and FoxO are the key regulators of cardiomyocyte hypertrophy and apoptosis in HCM. Using the model, we identified shared (e.g., activation of PGC1αby AMPK, and FHL1 by titin) and context-specific mechanisms (e.g., regulation of Ca2+sensitivity by titin in HCM patients) that could control genotype to phenotype transition in HCM across different species or mutations. We also predicted potential combination drug targets for HCM (e.g., mavacamten paired with ROS inhibitors) preventing or reversing HCM phenotype (i.e., hypertrophic growth, apoptosis, and metabolic remodeling) in cardiomyocytes. This study provides new insights into mechanisms linking genotype to phenotype in familial hypertrophic cardiomyopathy and offers a framework for assessing new treatments and exploring variations in HCM experimental models.

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Section: Heterogeneity In Hcmmentioning

confidence: 99%

Modeling Cardiomyocyte Signaling and Metabolism Predicts Genotype to Phenotype Mechanisms in Hypertrophic Cardiomyopathy

Khalilimeybodi,

Saucerman,

Rangamani

2023

Preprint

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“…It is reported that one of the most relevant consequences of overnutrition and obesity during early life is the development of insulin resistance [6], a condition associated with a decreased activation of the PI3K-Akt pathway in insulin-dependent tissues such as the liver skeletal muscle and adipose tissue, which results in an impaired uptake and storage of glucose, promoting hyperglycemia in the long term [13]. Moreover, since insulin also triggers a wide range of cardiovascular effects under physiological conditions, insulin resistance not only affects metabolic tissues but also the cardiovascular system [14].…”

Section: Introductionmentioning

confidence: 99%

Postnatal Overfeeding during Lactation Induces Endothelial Dysfunction and Cardiac Insulin Resistance in Adult Rats

Tejera-Muñoz,

Guerra-Menéndez,

Amor

et al. 2023

IJMS

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Early overnutrition is associated with cardiometabolic alterations in adulthood, likely attributed to reduced insulin sensitivity due to its crucial role in the cardiovascular system. This study aimed to assess the long-term effects of early overnutrition on the development of cardiovascular insulin resistance. An experimental childhood obesity model was established using male Sprague Dawley rats. Rats were organized into litters of 12 pups/mother (L12-Controls) or 3 pups/mother (L3-Overfed) at birth. After weaning, animals from L12 and L3 were housed three per cage and provided ad libitum access to food for 6 months. L3 rats exhibited elevated body weight, along with increased visceral, subcutaneous, and perivascular fat accumulation. However, heart weight at sacrifice was reduced in L3 rats. Furthermore, L3 rats displayed elevated serum levels of glucose, leptin, adiponectin, total lipids, and triglycerides compared to control rats. In the myocardium, overfed rats showed decreased IL-10 mRNA levels and alterations in contractility and heart rate in response to insulin. Similarly, aortic tissue exhibited modified gene expression of TNFα, iNOS, and IL-6. Additionally, L3 aortas exhibited endothelial dysfunction in response to acetylcholine, although insulin-induced relaxation remained unchanged compared to controls. At the molecular level, L3 rats displayed reduced Akt phosphorylation in response to insulin, both in myocardial and aortic tissues, whereas MAPK phosphorylation was elevated solely in the myocardium. Overfeeding during lactation in rats induces endothelial dysfunction and cardiac insulin resistance in adulthood, potentially contributing to the cardiovascular alterations observed in this experimental model.

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“…The heart, for example, expresses abundant insulin receptors and is considered an insulin-dependent organ that regulates cardiac metabolism and contractility in cardiomyocytes, fibroblasts, and endothelial cells. Pantazi et al [5] reviewed how the loss of the vital insulin signaling receptor substrates 1 and 2 (IRS1 and IRS2) is linked to insulin resistance and heart failure (HF). In both type 1 and type 2 diabetes mellitus (DM) patients, the workload of the left ventricle often increases, making heart failure an early sign of DM.…”

mentioning

confidence: 99%

Insulin Receptor Signaling in Health and Disease

2023

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Insulin Receptors and Insulin Action in the Heart: The Effects of Left Ventricular Assist Devices

Cited by 7 publications

References 69 publications

Modeling Cardiomyocyte Signaling and Metabolism Predicts Genotype to Phenotype Mechanisms in Hypertrophic Cardiomyopathy

Modeling Cardiomyocyte Signaling and Metabolism Predicts Genotype to Phenotype Mechanisms in Hypertrophic Cardiomyopathy

Postnatal Overfeeding during Lactation Induces Endothelial Dysfunction and Cardiac Insulin Resistance in Adult Rats

Insulin Receptor Signaling in Health and Disease

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