For years, females were thought of as smaller men with complex hormonal cycles; as a result, females have been largely excluded from preclinical and clinical research. However, in the last ten years, ...with the increased focus on sex as a biological variable, it has become clear that this is not the case, and in fact, male and female cardiovascular biology and cardiac stress responses differ substantially. Premenopausal women are protected from cardiovascular diseases, such as myocardial infarction and resultant heart failure, having preserved cardiac function, reduced adverse remodeling, and increased survival. Many underlying biological processes that contribute to ventricular remodeling differ between the sexes, such as cellular metabolism; immune cell responses; cardiac fibrosis and extracellular matrix remodeling; cardiomyocyte dysfunction; and endothelial biology; however, it is unclear how these changes afford protection to the female heart. Although many of these changes are dependent on protection provided by female sex hormones, several of these changes occur independent of sex hormones, suggesting that the nature of these changes is more complex than initially thought. This may be why studies focused on the cardiovascular benefits of hormone replacement therapy in post-menopausal women have provided mixed results. Some of the complexity likely stems from the fact that the cellular composition of the heart is sexually dimorphic and that in the setting of MI, different subpopulations of these cell types are apparent. Despite the documented sex-differences in cardiovascular (patho)physiology, the underlying mechanisms that contribute are largely unknown due to inconsistent findings amongst investigators and, in some cases, lack of rigor in reporting and consideration of sex-dependent variables. Therefore, this review aims to describe current understanding of the sex-dependent differences in the myocardium in response to physiological and pathological stressors, with a focus on the sex-dependent differences that contribute to post-infarction remodeling and resultant functional decline.
O-GlcNAcylation and cardiovascular disease Wright, JaLessa N; Collins, Helen E; Wende, Adam R ...
Biochemical Society transactions,
04/2017, Letnik:
45, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The post-translational modification of serine and threonine residues of proteins found in numerous subcellular locations by
-linked
-acetylglucosamine (
-GlcNAc) is emerging as a key mediator of many ...cardiovascular pathophysiological processes. Early studies implicated increased protein O-GlcNAcylation as contributing to the cardiovascular complications associated with diabetes, whereas subsequent studies demonstrated that acute increases in
-GlcNAc levels were protective against ischemia/reperfusion injury. There is now a growing understanding that
-GlcNAc modification of proteins influences numerous cellular functions, including transcription, protein turnover, calcium handling, and bioenergetics. As a result, a more nuanced view of the role of protein O-GlcNAcylation in the cardiovascular system is emerging along with the recognition that it is required for normal cellular function and homeostasis. Consequently, the impact of changes in
-GlcNAc cycling due to stress or disease on the heart is complex and highly dependent on the specific context of these events. The goal of this review is to provide an overview of some of the more recent advances in our understanding of the role O-GlcNAcylation plays in mediating cardiovascular function and disease.
Our understanding of the role of protein O-GlcNAcylation in the regulation of the cardiovascular system has increased rapidly in recent years. Studies have linked increased O-GlcNAc levels to glucose ...toxicity and diabetic complications; conversely, acute activation of O-GlcNAcylation has been shown to be cardioprotective. However, it is also increasingly evident that O-GlcNAc turnover plays a central role in the delicate regulation of the cardiovascular system. Therefore, the goals of this minireview are to summarize our current understanding of how changes in O-GlcNAcylation influence cardiovascular pathophysiology and to highlight the evidence that O-GlcNAc cycling is critical for normal function of the cardiovascular system.
Wild animals are used in scientific research in a wide variety of contexts both in situ and ex situ. Guidelines for best practice, where they exist, are not always clearly linked to animal welfare ...and may instead have their origins in practicality. This is complicated by a lack of clarity about indicators of welfare for wild animals, and to what extent a researcher should intervene in cases of compromised welfare.
This Primer highlights and discusses the broad topic of wild animal welfare and the ethics of using wild animals in scientific research, both in the wild and in controlled conditions. Throughout, we discuss issues associated with the capture, handling, housing and experimental approaches for species occupying varied habitats, in both vertebrates and invertebrates (principally insects, crustaceans and molluscs).
We highlight where data on the impacts of wild animal research are lacking and provide suggestive guidance to help direct, prepare and mitigate potential welfare issues, including the consideration of end‐points and the ethical framework around euthanasia.
We conclude with a series of recommendations for researchers to implement from the design stage of any study that uses animals, right through to publication, and discuss the role of journals in promoting better reporting of wild animal studies, ultimately to the benefit of wild animal welfare.
Store-operated Ca²⁺ entry (SOCE) is critical for Ca²⁺ signaling in nonexcitable cells; however, its role in the regulation of cardiomyocyte Ca²⁺ homeostasis has only recently been investigated. The ...increased understanding of the role of stromal interaction molecule 1 (STIM1) in regulating SOCE combined with recent studies demonstrating the presence of STIM1 in cardiomyocytes provides support that this pathway co-exists in the heart with the more widely recognized Ca²⁺ handling pathways associated with excitation-contraction coupling. There is now substantial evidence that STIM1-mediated SOCE plays a key role in mediating cardiomyocyte hypertrophy, both in vitro and in vivo, and there is growing support for the contribution of SOCE to Ca²⁺ overload associated with ischemia/reperfusion injury. Here, we provide an overview of our current understanding of the molecular regulation of SOCE and discuss the evidence supporting the role of STIM1/Orai1-mediated SOCE in regulating cardiomyocyte function.
The post-translational modification of serine and threonine residues of nuclear, cytosolic, and mitochondrial proteins by O-linked β-N-acetyl glucosamine (O-GlcNAc) has long been seen as an important ...regulatory mechanism in the cardiovascular system. O-GlcNAcylation of cardiac proteins has been shown to contribute to the regulation of transcription, metabolism, mitochondrial function, protein quality control and turnover, autophagy, and calcium handling. In the heart, acute increases in O-GlcNAc have been associated with cardioprotection, such as those observed during ischemia/reperfusion. Conversely, chronic increases in O-GlcNAc, often associated with diabetes and nutrient excess, have been shown to contribute to cardiac dysfunction. Traditionally, many studies have linked changes in O-GlcNAc with nutrient availability and as such O-GlcNAcylation is often seen as a nutrient driven process. However, emerging evidence suggests that O-GlcNAcylation may also be regulated by non-nutrient dependent mechanisms, such as transcriptional and post-translational regulation. Therefore, the goals of this review are to provide an overview of the impact of O-GlcNAcylation in the cardiovascular system, how this is regulated and to discuss the emergence of regulatory mechanisms other than nutrient availability.
•Modification of proteins by O-linked β-N-acetyl glucosamine (O-GlcNAc) have diverse effects on cardiac function.•Changes in O-GlcNAc levels are frequently associated with alterations in nutrient availability.•New studies indicate that O-GlcNAc levels are also regulated by nutrient-independent mechanisms.•We provide an overview of the role of O-GlcNAc in the cardiovascular system and how it is regulated.
Circadian clocks are cell autonomous, transcriptionally based, molecular mechanisms that confer the selective advantage of anticipation, enabling cells/organs to respond to environmental factors in a ...temporally appropriate manner. Critical to circadian clock function are 2 transcription factors, CLOCK and BMAL1. The purpose of the present study was to reveal novel physiologic functions of BMAL1 in the heart, as well as to determine the pathologic consequences of chronic disruption of this circadian clock component. To address this goal, we generated cardiomyocyte-specific Bmal1 knockout (CBK) mice. Following validation of the CBK model, combined microarray and in silico analyses were performed, identifying 19 putative direct BMAL1 target genes, which included a number of metabolic (e.g., β-hydroxybutyrate dehydrogenase 1 Bdh1) and signaling (e.g., the p85α regulatory subunit of phosphatidylinositol 3-kinase Pik3r1) genes. Results from subsequent validation studies were consistent with regulation of Bdh1 and Pik3r1 by BMAL1, with predicted impairments in ketone body metabolism and signaling observed in CBK hearts. Furthermore, CBK hearts exhibited depressed glucose utilization, as well as a differential response to a physiologic metabolic stress (i.e., fasting). Consistent with BMAL1 influencing critical functions in the heart, echocardiographic, gravimetric, histologic, and molecular analyses revealed age-onset development of dilated cardiomyopathy in CBK mice, which was associated with a severe reduction in life span. Collectively, our studies reveal that BMAL1 influences metabolism, signaling, and contractile function of the heart.
Mitochondria morphology and function, and their quality control by mitophagy, are essential for heart function. We investigated whether these are influenced by time of the day (TOD), sex, and fed or ...fasting status, using transmission electron microscopy (EM), mitochondrial electron transport chain (ETC) activity, and mito-QC reporter mice. We observed peak mitochondrial number at ZT8 in the fed state, which was dependent on the intrinsic cardiac circadian clock, as hearts from cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit different TOD responses. In contrast to mitochondrial number, mitochondrial ETC activities do not fluctuate across TOD, but decrease immediately and significantly in response to fasting. Concurrent with the loss of ETC activities, ETC proteins were decreased with fasting, simultaneous with significant increases of mitophagy, mitochondrial antioxidant protein SOD2, and the fission protein DRP1. Fasting-induced mitophagy was lost in CBK mice, indicating a direct role of BMAL1 in regulating mitophagy. This is the first of its kind report to demonstrate the interactions between sex, fasting, and TOD on cardiac mitochondrial structure, function and mitophagy. These studies provide a foundation for future investigations of mitochondrial functional perturbation in aging and heart diseases.
The goal of the present study was to characterize changes in mitochondrial respiration in the maternal heart during pregnancy and after birth. Timed pregnancy studies were performed in 12-wk-old ...female FVB/NJ mice, and cardiac mitochondria were isolated from the following groups of mice: nonpregnant (NP), midpregnancy (MP), late pregnancy (LP), and 1-wk postbirth (PB). Similar to our previous studies, we observed increased heart size during all stages of pregnancy (e.g., MP and LP) and postbirth (e.g., PB) compared with NP mice. Differential cardiac gene and protein expression analyses revealed changes in several mitochondrial transcripts at LP and PB, including several mitochondrial complex subunits and members of the
family, important for mitochondrial substrate transport. Respirometry revealed that pyruvate- and glutamate-supported state 3 respiration was significantly higher in PB vs. LP mitochondria, with respiratory control ratio (RCR) values higher in PB mitochondria. In addition, we found that PB mitochondria respired more avidly when given 3-hydroxybutyrate (3-OHB) than mitochondria from NP, MP, and LP hearts, with no differences in RCR. These increases in respiration in PB hearts occurred independent of changes in mitochondrial yield but were associated with higher abundance of 3-hydroxybutyrate dehydrogenase 1. Collectively, these findings suggest that, after birth, maternal cardiac mitochondria have an increased capacity to use 3-OHB, pyruvate, and glutamate as energy sources; however, increases in mitochondrial efficiency in the postpartum heart appear limited to carbohydrate and amino acid metabolism.
Few studies have detailed the physiological adaptations that occur in the maternal heart. We and others have shown that pregnancy-induced cardiac growth is associated with significant changes in cardiac metabolism. Here, we examined mitochondrial respiration and substrate preference in isolated mitochondria from the maternal heart. We show that following birth, cardiac mitochondria are "primed" to respire on carbohydrate, amino acid, and ketone bodies. However, heightened respiratory efficiency is observed only with carbohydrate and amino acid sources. These results suggest that significant changes in mitochondrial respiration occur in the maternal heart in the postpartum period.
Exercise training can promote physiological cardiac growth, which has been suggested to involve changes in glucose metabolism to facilitate hypertrophy of cardiomyocytes. In this study, we used a ...dietary, in vivo isotope labeling approach to examine how exercise training influences the metabolic fate of carbon derived from dietary glucose in the heart during acute, active, and established phases of exercise-induced cardiac growth. Male and female FVB/NJ mice were subjected to treadmill running for up to 4 weeks and cardiac growth was assessed by gravimetry. Cardiac metabolic responses to exercise were assessed via in vivo tracing of 13C6-glucose via mass spectrometry and nuclear magnetic resonance. We found that the half-maximal cardiac growth response was achieved by approximately 1 week of daily exercise training, with near maximal growth observed in male mice with 2 weeks of training; however, female mice were recalcitrant to exercise-induced cardiac growth and required a higher daily intensity of exercise training to achieve significant, albeit modest, increases in cardiac mass. We also found that increases in the energy charge of adenylate and guanylate nucleotide pools precede exercise-induced changes in cardiac size and were associated with higher glucose tracer enrichment in the TCA pool and in amino acids (aspartate, glutamate) sourced by TCA intermediates. Our data also indicate that the activity of collateral biosynthetic pathways of glucose metabolism may not be markedly altered by exercise. Overall, this study provides evidence that metabolic remodeling in the form of heightened energy charge and increased TCA cycle activity and cataplerosis precedes cardiac growth caused by exercise training in male mice.
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•Treadmill exercise promotes cardiac growth in male FVB/NJ mice during the first two weeks of training•Female FVB/NJ mice require a higher exercise training intensity than male mice to elicit marginal cardiac growth•Exercise augments energy charge, Krebs cycle activity, and cataplerosis before and during active cardiac growth•Differences in metabolism caused by exercise recede upon establishment of the cardiac growth phenotype
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