Background— Diabetes-associated cardiac dysfunction is associated with mitochondrial dysfunction and oxidative stress, which may contribute to left ventricular dysfunction. The contribution of altered myocardial insulin action, independent of associated changes in systemic metabolism, is incompletely understood. The present study tested the hypothesis that perinatal loss of insulin signaling in the heart impairs mitochondrial function. Methods and Results— In 8-week-old mice with cardiomyocyte deletion of insulin receptors (CIRKO), inotropic reserves were reduced, and mitochondria manifested respiratory defects for pyruvate that was associated with proportionate reductions in catalytic subunits of pyruvate dehydrogenase. Progressive age-dependent defects in oxygen consumption and ATP synthesis with the substrate glutamate and the fatty acid derivative palmitoyl-carnitine were observed. Mitochondria also were uncoupled when exposed to palmitoyl-carnitine, in part as a result of increased reactive oxygen species production and oxidative stress. Although proteomic and genomic approaches revealed a reduction in subsets of genes and proteins related to oxidative phosphorylation, no reductions in maximal activities of mitochondrial electron transport chain complexes were found. However, a disproportionate reduction in tricarboxylic acid cycle and fatty acid oxidation proteins in mitochondria suggests that defects in fatty acid and pyruvate metabolism and tricarboxylic acid flux may explain the mitochondrial dysfunction observed. Conclusions— Impaired myocardial insulin signaling promotes oxidative stress and mitochondrial uncoupling, which, together with reduced tricarboxylic acid and fatty acid oxidative capacity, impairs mitochondrial energetics. This study identifies specific contributions of impaired insulin action to mitochondrial dysfunction in the heart.

Contribution Of Impaired Myocardial InsulinSignaling To Mitochondrial Dysfunction AndOxidative Stress In The Heart

https://www.cell.com/cell-metabolism/pdf/S1550-4131(15)00277-6.pdf

Calcium Homeostasis and Organelle Function in the Pathogenesis of Obesity and Diabetes

Reactive oxygen species (ROS) are highly reactive chemical species containing oxygen, controlled by both enzymatic and nonenzymatic antioxidant defense systems. In the heart, ROS play an important role in cell homeostasis, by modulating cell proliferation, differentiation, and excitation-contraction coupling. Oxidative stress occurs when ROS production exceeds the buffering capacity of the antioxidant defense systems, leading to cellular and molecular abnormalities, ultimately resulting in cardiac dysfunction. In this review, we will discuss the physiological sources of ROS in the heart, the mechanisms of oxidative stress-related myocardial injury, and the implications of experimental studies and clinical trials with antioxidant therapies in cardiovascular diseases.

/pdf/the-role-of-oxidative-stress-in-cardiac-disease-from-3omv3l9caa.pdf

The Role of Oxidative Stress in Cardiac Disease: From Physiological Response to Injury Factor

The prevalence of heart failure is on the rise and imposes a major health threat, in part, due to the rapidly increased prevalence of overweight and obesity. To this point, epidemiological, clinical, and experimental evidence supports the existence of a unique disease entity termed "obesity cardiomyopathy," which develops independent of hypertension, coronary heart disease, and other heart diseases. Our contemporary review evaluates the evidence for this pathological condition, examines putative responsible mechanisms, and discusses therapeutic options for this disorder. Clinical findings have consolidated the presence of left ventricular dysfunction in obesity. Experimental investigations have uncovered pathophysiological changes in myocardial structure and function in genetically predisposed and diet-induced obesity. Indeed, contemporary evidence consolidates a wide array of cellular and molecular mechanisms underlying the etiology of obesity cardiomyopathy including adipose tissue dysfunction, systemic inflammation, metabolic disturbances (insulin resistance, abnormal glucose transport, spillover of free fatty acids, lipotoxicity, and amino acid derangement), altered intracellular especially mitochondrial Ca2+ homeostasis, oxidative stress, autophagy/mitophagy defect, myocardial fibrosis, dampened coronary flow reserve, coronary microvascular disease (microangiopathy), and endothelial impairment. Given the important role of obesity in the increased risk of heart failure, especially that with preserved systolic function and the recent rises in COVID-19-associated cardiovascular mortality, this review should provide compelling evidence for the presence of obesity cardiomyopathy, independent of various comorbid conditions, underlying mechanisms, and offer new insights into potential therapeutic approaches (pharmacological and lifestyle modification) for the clinical management of obesity cardiomyopathy.

https://journals.physiology.org/doi/pdf/10.1152/physrev.00030.2020

Obesity Cardiomyopathy: Evidence, Mechanisms and Therapeutic Implications.

Although sleep appears to be broadly conserved in animals, the physiological functions of sleep remain unclear. In this study, we sought to identify a physiological defect common to a diverse group of short-sleeping Drosophila mutants, which might provide insight into the function and regulation of sleep. We found that these short-sleeping mutants share a common phenotype of sensitivity to acute oxidative stress, exhibiting shorter survival times than controls. We further showed that increasing sleep in wild-type flies using genetic or pharmacological approaches increases survival after oxidative challenge. Moreover, reducing oxidative stress in the neurons of wild-type flies by overexpression of antioxidant genes reduces the amount of sleep. Together, these results support the hypothesis that a key function of sleep is to defend against oxidative stress and also point to a reciprocal role for reactive oxygen species (ROS) in neurons in the regulation of sleep.

/pdf/a-bidirectional-relationship-between-sleep-and-oxidative-4zwrmcjv4d.pdf

A bidirectional relationship between sleep and oxidative stress in Drosophila.

Ca+ mishandling due to impaired activity of cardiac sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) has been associated with the development of left ventricular diastolic dysfunction in insulin-...

https://www.physiology.org/doi/pdf/10.1152/ajpheart.00211.2013

Oxidative stress in cardiomyocytes contributes to decreased SERCA2a activity in rats with metabolic syndrome.

Ca2+ mishandling and cardiac dysfunction in obesity and insulin resistance: Role of oxidative stress

Obesity, defined as a harmful accumulation of body fat, increases the risk of cardiac hypertrophy, which leads to heart failure (HF). Obesity often coexists with hypertension, a condition that aggravates cardiac hypertrophy and accelerates the progression of HF. The cellular and molecular mechanisms involved in cardiac hypertrophy during obesity, and those that explain synergic effect of obesity and hypertension on cardiac hypertrophy are still an issue of investigation. So far, evidence suggests that obesity promotes cellular events related to insulin resistance, neurohormonal over-activation, oxidative stress, chronic inflammation and perturbation of cellular signaling, which are some of the processes involved in the onset of cardiac hypertrophy and hypertension, and indeed the exacerbation of these events appears to explain, in part, the worsening of cardiac hypertrophy when obesity is accompanied by hypertension. In this chapter, we analyze data that may help to clarify the participation of the complex interconnecting mechanisms that are evoked by obesity and hypertension, when allied together to induce cardiac hypertrophy. Better understanding of these mechanisms will allow us to have an improved management of obesity and obesity-related hypertension, as well as to achieve more effective prophylactic therapies and opportune diagnosis of these clinical conditions.

Tzindilu Molina-Muñoz

Papers

Oxidative stress in cardiomyocytes contributes to decreased SERCA2a activity in rats with metabolic syndrome.

Ca2+ mishandling and cardiac dysfunction in obesity and insulin resistance: Role of oxidative stress

Cellular and Molecular Mechanisms Contributing to Cardiac Hypertrophy in Obesity and Obesity-Related Hypertension

Oxidative stress in cardiomyocytes contributes to

FailureCardiac Myocyte Ca Regulation In Heart