Reactive Oxygen Species Induced Pathways in Heart Failure Pathogenesis and Potential Therapeutic Strategies

Mongirdienė, Aušra; Skrodenis, L; Varoneckaitė, Leila; Mierkytė, Gerda; Gerulis, Justinas

doi:10.3390/biomedicines10030602

Cited by 32 publications

(18 citation statements)

References 303 publications

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“…For example, the timing and duration of ROS inhibition are crucial, as long-term ROS inhibition might interfere with the physiological roles of ROS, potentially causing side effects [70]. Moreover, given the heterogeneous nature of HCM and complex ROS signaling, ROS inhibition might affect individuals differently [22, 65, 67], potentially contributing to the limited effectiveness of general antioxidant treatments for patients with heart disease [71].…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

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

Khalilimeybodi,

Saucerman,

Rangamani

2023

Preprint

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“…(53) Following these reports, several clinical studies on the adminis-Table 1. Diseases involving reactive oxygen species and free radicals Brain/neurological disorders cerebral infarction, (4) diabetic neuropathy, (7) Alzheimer's disease/dementia, (8)(9)(10)(11) Parkinson's disease (12,13) Respiratory diseases pneumonia/infections, (14) smoking, (15) bronchial asthma, (16) chronic obstructive pulmonary disease (17) Cardiovascular diseases myocardial infarction, (18) arteriosclerosis, (19) ischemia-reperfusion injury, (18) heart failure, (20) cardiomyopathy (21) Gastrointestinal disorders gastric ulcer, (22) non-alcoholic steatohepatitis, (3) inflammatory bowel disease/ulcerative colitis (23) Endocrine disorders diabetes, (24) hyperlipidemia (25) Urologic diseases chronic nephritis, diabetic nephropathy, (26) nephrotic syndrome (27) Ophthalmic disorders cataract, (28) glaucoma, (29) age-related macular degeneration, (30) diabetic retinopathy, (24) retinopathy of prematurity, (31) dry eye (32) Other diseases cancer, (33) atopic dermatitis, (34) sunlight dermatitis, (35) chronic granulomatosis, (36) rheumatoid arthritis, (37) systemic lupus erythematosus, (37) chronic fatigue syndrome, (38) aging, (39) stains/wrinkles…”

Section: Disease Treatment By Suppressing Oxidative Stress By Antioxi...mentioning

confidence: 99%

Application of regulation of reactive oxygen species and lipid peroxidation to disease treatment

Shichiri

Suzuki

Isegawa

et al. 2023

J. Clin. Biochem. Nutr.

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Although many diseases in which reactive oxygen species (ROS) and free radicals are involved in their pathogenesis are known, and antioxidants that effectively capture ROS have been identified and developed, there are only a few diseases for which antioxidants have been used for treatment. Here, we discuss on the following four concepts regarding the development of applications for disease treatment by regulating ROS, free radicals, and lipid oxidation with the findings of our research and previous reports. Concept 1) Utilization of antioxidants for disease treatment. In particular, the importance of the timing of starting antioxidant will be discussed. Concept 2) Therapeutic strategies using ROS and free radicals. Methods of inducing ferroptosis, which has been advocated as an iron-dependent cell death, are mentioned. Concept 3) Treatment with drugs that inhibit the synthesis of lipid mediators. In addition to the reduction of inflammatory lipid mediators by inhibiting cyclooxygenase and leukotriene synthesis, we will introduce the possibility of disease treatment with lipoxygenase inhibitors. Concept 4) Disease treatment by inducing the production of useful lipid mediators for disease control. We describe the treatment of inflammatory diseases utilizing pro-resolving mediators and propose potential compounds that activate lipoxygenase to produce these beneficial mediators.

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“…Nitric oxide (NO), which is predominantly generated in the endothelium by eNOS, has potent vasodilatory activity in the coronary and peripheral vasculature via the activation of soluble guanylate cyclase (sGC) in vascular smooth muscle cells [ 159 , 160 ] ( Figure 3 ). NOX-generated ROS interfere with the catalytic cycle of NOS enzymes, resulting in the production of superoxide rather than NO that reduces NO bioavailability, impairing cGMP-dependent vascular smooth muscle relaxation, protein kinase G (PKG) signaling, and further contributing to oxidative stress [ 21 , 36 , 161 ]. Additionally, the uncoupling of NOS enzymes impairs myofilament relaxation and diastolic function by dampening the PKG-mediated phosphorylation of titin [ 21 , 36 , 162 , 163 ].…”

Section: Nadph Oxidases and Nitric Oxide (No) Signalingmentioning

confidence: 99%

“…The interplay between oxidative stress and NO production is complex but basic science studies and clinical data suggest that both NOX and NOS enzymes and oxidative and nitrosative stress play important roles in HFpEF. The NOX-mediated uncoupling of NOS enzymes in the vasculature could limit NO production and further promote the generation of ROS and reactive nitrogen species, oxidative tissue damage, and pathogenic redox signaling [ 21 , 36 , 161 ]. However, enhanced nitrosative stress is emerging as a hallmark and defining feature of HFpEF myocardium that occurs largely as a consequence of the induction of iNOS and nNOS levels and activity in cardiac myocytes [ 1 , 7 , 169 ].…”

Section: Nadph Oxidases and Nitric Oxide (No) Signalingmentioning

confidence: 99%

NADPH Oxidases in Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction

et al. 2022

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Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases regulate production of reactive oxygen species (ROS) that cause oxidative damage to cellular components but also regulate redox signaling in many cell types with essential functions in the cardiovascular system. Research over the past couple of decades has uncovered mechanisms by which NADPH oxidase (NOX) enzymes regulate oxidative stress and compartmentalize intracellular signaling in endothelial cells, smooth muscle cells, macrophages, cardiomyocytes, fibroblasts, and other cell types. NOX2 and NOX4, for example, regulate distinct redox signaling mechanisms in cardiac myocytes pertinent to the onset and progression of cardiac hypertrophy and heart failure. Heart failure with preserved ejection fraction (HFpEF), which accounts for at least half of all heart failure cases and has few effective treatments to date, is classically associated with ventricular diastolic dysfunction, i.e., defects in ventricular relaxation and/or filling. However, HFpEF afflicts multiple organ systems and is associated with systemic pathologies including inflammation, oxidative stress, arterial stiffening, cardiac fibrosis, and renal, adipose tissue, and skeletal muscle dysfunction. Basic science studies and clinical data suggest a role for systemic and myocardial oxidative stress in HFpEF, and evidence from animal models demonstrates the critical functions of NOX enzymes in diastolic function and several HFpEF-associated comorbidities. Here, we discuss the roles of NOX enzymes in cardiovascular cells that are pertinent to the development and progression of diastolic dysfunction and HFpEF and outline potential clinical implications.

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Reactive Oxygen Species Induced Pathways in Heart Failure Pathogenesis and Potential Therapeutic Strategies

Cited by 32 publications

References 303 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

Application of regulation of reactive oxygen species and lipid peroxidation to disease treatment

NADPH Oxidases in Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction

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