scholarly journals Mitochondrial Pathobiology and Metabolic Remodeling in Progression to Overt Systolic Heart Failure

2020 ◽  
Vol 9 (11) ◽  
pp. 3582
Author(s):  
Antoine H. Chaanine ◽  
Thierry H. LeJemtel ◽  
Patrice Delafontaine
Keyword(s):  
Heart Failure ◽  
Cardiac Myocyte ◽  
Ion Homeostasis ◽  
Systolic Heart Failure ◽  
Redox Balance ◽  
High Energy ◽  
Mitochondrial Morphology ◽  
Metabolic Remodeling ◽  
Dynamics And Function ◽  
And Function

The mitochondria are mostly abundant in the heart, a beating organ of high- energy demands. Their function extends beyond being a power plant of the cell including redox balance, ion homeostasis and metabolism. They are dynamic organelles that are tethered to neighboring structures, especially the endoplasmic reticulum. Together, they constitute a functional unit implicated in complex physiological and pathophysiological processes. Their topology in the cell, the cardiac myocyte in particular, places them at the hub of signaling and calcium homeostasis, making them master regulators of cell survival or cell death. Perturbations in mitochondrial function play a central role in the pathophysiology of myocardial remodeling and progression of heart failure. In this minireview, we summarize important pathophysiological mechanisms, pertaining to mitochondrial morphology, dynamics and function, which take place in compensated hypertrophy and in progression to overt systolic heart failure. Published work in the last few years has expanded our understanding of these important mechanisms; a key prerequisite to identifying therapeutic strategies targeting mitochondrial dysfunction in heart failure.

scholarly journals FOXO3a regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress

2016 ◽  
Vol 311 (6) ◽  
pp. H1540-H1559 ◽  
Author(s):  
Antoine H. Chaanine ◽  
Erik Kohlbrenner ◽  
Scott I. Gamb ◽  
Adam J. Guenzel ◽  
Katherine Klaus ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dynamics ◽  
Left Ventricular ◽  
Attractive Potential ◽  
Mitochondrial Morphology ◽  
Cardiac Stress ◽  
Virus Serotype ◽  
Dynamics And Function ◽  
And Function

The forkhead box O3a (FOXO3a) transcription factor has been shown to regulate glucose metabolism, muscle atrophy, and cell death in postmitotic cells. Its role in regulation of mitochondrial and myocardial function is not well studied. Based on previous work, we hypothesized that FOXO3a, through BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3), modulates mitochondrial morphology and function in heart failure (HF). We modulated the FOXO3a-BNIP3 pathway in normal and phenylephrine (PE)-stressed adult cardiomyocytes (ACM) in vitro and developed a cardiotropic adeno-associated virus serotype 9 encoding dominant-negative FOXO3a (AAV9.dn-FX3a) for gene delivery in a rat model of HF with preserved ejection fraction (HFpEF). We found that FOXO3a upregulates BNIP3 expression in normal and PE-stressed ACM, with subsequent increases in mitochondrial Ca2+, leading to decreased mitochondrial membrane potential, mitochondrial fragmentation, and apoptosis. Whereas dn-FX3a attenuated the increase in BNIP3 expression and its consequences in PE-stressed ACM, AAV9.dn-FX3a delivery in an experimental model of HFpEF decreased BNIP3 expression, reversed adverse left ventricular remodeling, and improved left ventricular systolic and, particularly, diastolic function, with improvements in mitochondrial structure and function. Moreover, AAV9.dn-FX3a restored phospholamban phosphorylation at S16 and enhanced dynamin-related protein 1 phosphorylation at S637. Furthermore, FOXO3a upregulates maladaptive genes involved in mitochondrial apoptosis, autophagy, and cardiac atrophy. We conclude that FOXO3a activation in cardiac stress is maladaptive, in that it modulates Ca2+ cycling, Ca2+ homeostasis, and mitochondrial dynamics and function. Our results suggest an important role of FOXO3a in HF, making it an attractive potential therapeutic target. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/role-of-foxo3a-in-heart-failure/ .

scholarly journals A role for keratins in supporting mitochondrial organization and function in skin keratinocytes

2019 ◽  
Author(s):  
Kaylee Steen ◽  
Desu Chen ◽  
Fengrong Wang ◽  
Song Chen ◽  
Surinder Kumar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Regulation ◽  
Mouse Skin ◽  
Mitochondrial Morphology ◽  
Null Mouse ◽  
Embryonic Mouse ◽  
Atp Production ◽  
Skin Keratinocytes ◽  
Dynamics And Function ◽  
And Function

AbstractMitochondria fulfill essential roles in ATP production, metabolic regulation, calcium signaling, generation of reactive oxygen species (ROS) and additional determinants of cellular health. Recent studies have highlighted a role for mitochondria during cell differentiation, including in skin epidermis. The observation of oxidative stress in keratinocytes from Krt16 null mouse skin, a model for pachyonychia congenita (PC)-associated palmoplantar keratoderma, prompted us to examine the role of Keratin (K) 16 protein and its partner K6 in regulating the structure and function of mitochondria. Electron microscopy revealed major anomalies in mitochondrial ultrastructure in late stage, E18.5, Krt6a/Krt6b null embryonic mouse skin. Follow-up studies utilizing biochemical, metabolic, and live imaging readouts showed that, relative to controls, skin keratinocytes null for Krt6a/Krt6b or Krt16 exhibit elevated ROS, reduced mitochondrial respiration, intracellular distribution differences and altered movement of mitochondria within the cell. These findings highlight a novel role for K6 and K16 in regulating mitochondrial morphology, dynamics and function and shed new light on the causes of oxidative stress observed in PC and related keratin-based skin disorders.

scholarly journals Neuregulins: protective and reparative growth factors in multiple forms of cardiovascular disease

2020 ◽  
Vol 134 (19) ◽  
pp. 2623-2643
Author(s):  
Andrew Geissler ◽  
Sergey Ryzhov ◽  
Douglas B. Sawyer
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Tyrosine Kinases ◽  
Cardiac Myocyte ◽  
Diastolic Heart Failure ◽  
Systolic Heart Failure ◽  
Circulatory System ◽  
Cardiovascular Responses ◽  
Adaptive Responses ◽  
Beneficial Effects

Abstract Neuregulins (NRGs) are protein ligands that act through ErbB receptor tyrosine kinases to regulate tissue morphogenesis, plasticity, and adaptive responses to physiologic needs in multiple tissues, including the heart and circulatory system. The role of NRG/ErbB signaling in cardiovascular biology, and how it responds to physiologic and pathologic stresses is a rapidly evolving field. While initial concepts focused on the role that NRG may play in regulating cardiac myocyte responses, including cell survival, growth, adaptation to stress, and proliferation, emerging data support a broader role for NRGs in the regulation of metabolism, inflammation, and fibrosis in response to injury. The constellation of effects modulated by NRGs may account for the findings that two distinct forms of recombinant NRG-1 have beneficial effects on cardiac function in humans with systolic heart failure. NRG-4 has recently emerged as an adipokine with similar potential to regulate cardiovascular responses to inflammation and injury. Beyond systolic heart failure, NRGs appear to have beneficial effects in diastolic heart failure, prevention of atherosclerosis, preventing adverse effects on diabetes on the heart and vasculature, including atherosclerosis, as well as the cardiac dysfunction associated with sepsis. Collectively, this literature supports the further examination of how this developmentally critical signaling system functions and how it might be leveraged to treat cardiovascular disease.

scholarly journals Reversal of heart failure in a chemogenetic model of persistent cardiac redox stress

2019 ◽  
Vol 317 (3) ◽  
pp. H617-H626 ◽  
Author(s):  
Andrea Sorrentino ◽  
Benjamin Steinhorn ◽  
Luca Troncone ◽  
Seyed Soheil Saeedi Saravi ◽  
Sachin Badole ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Myocyte ◽  
Ang Ii ◽  
Failure Model ◽  
Redox Stress ◽  
Amino Acid Oxidase ◽  
Chronic Oxidative Stress ◽  
Metabolic Remodeling ◽  
Heart Failure Model

We previously described a novel “chemogenetic” animal model of heart failure that recapitulates a characteristic feature commonly found in human heart failure: chronic oxidative stress. This heart failure model uses a chemogenetic approach to activate a recombinant yeast d-amino acid oxidase in rat hearts in vivo to generate oxidative stress, which then rapidly leads to the development of a dilated cardiomyopathy. Here we apply this new model to drug testing by studying its response to treatment with the angiotensin II (ANG II) receptor blocker valsartan, administered either alone or with the neprilysin inhibitor sacubitril. Echocardiographic and [18F]fluorodeoxyglucose positron emission tomographic imaging revealed that valsartan in the presence or absence of sacubitril reverses the anatomical and metabolic remodeling induced by chronic oxidative stress. Markers of oxidative stress, mitochondrial function, and apoptosis, as well as classical heart failure biomarkers, also normalized following drug treatments despite the persistence of cardiac fibrosis. These findings provide evidence that chemogenetic heart failure is rapidly reversible by drug treatment, setting the stage for the study of novel heart failure therapeutics in this model. The ability of ANG II blockade and neprilysin inhibition to reverse heart failure induced by chronic oxidative stress identifies a central role for cardiac myocyte angiotensin receptors in the pathobiology of cardiac dysfunction caused by oxidative stress. NEW & NOTEWORTHY The chemogenetic approach allows us to distinguish cardiac myocyte-specific pathology from the pleiotropic changes that are characteristic of other “interventional” animal models of heart failure. These features of the chemogenetic heart failure model facilitate the analysis of drug effects on the progression and regression of ventricular remodeling, fibrosis, and dysfunctional signal transduction. Chemogenetic approaches will be highly informative in the study of the roles of redox stress in heart failure providing an opportunity for the identification of novel therapeutic targets.

Abstract 069: Mitochondrial Mechanisms Of Reverse Remodeling In Heart Failure

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Preeti Ahuja ◽  
William R MacLellan ◽  
Yibin Wang
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Reverse Remodeling ◽  
Ventricular Assist ◽  
Hypertrophic Response ◽  
Mtdna Deletions ◽  
And Function

Enhancement of myocardial mitochondrial (mt) function resulting in efficient energy production by means of Left ventricular assist device (LVAD) has been suggested in heart failure (HF) which could have important clinical implications and may represent a novel therapeutic target. However, the basis for this improvement remains unknown. To characterize mt biogenesis, mt genomic integrity and mitophagy in reversing pathological remodeling, we investigated LV tissue from post-LVAD human hearts and after reversal of transaortic constriction (TAC) in mice. In Post-LVAD human hearts there was increased expression of mt fusion and biogenesis, mtDNA levels were normalized and deletion mutation rates were significantly reduced with reverse remodeling and these changes were associated with enhancement of mt ETC complex I and II activities and improved cardiac-myocyte morphology. To better understand the mechanisms underlying mt repair/remodeling with LVAD support, we developed a model of aortic banding (AB) and debanding (DB) in mice. C57BL/6 mice were subjected to 2 weeks of AB and subsequent DB for period of 1 to 20 days and cardiac function and hypertrophy were evaluated by echocardiography and real-time PCR, respectively. Compared with control animals, mice that had undergone banding had a robust hypertrophic response with decline in cardiac function. These parameters were reversed following removal of pressure overload by DB. Even 1 day of unloading led to significant increase in the expression of mt fusion and biogenesis genes. Hearts from AB (2 weeks) mice showed a 3.7-fold (P<0.05) increase in frequency of mtDNA deletions. However, mtDNA deletions were significantly reduced in frequency with DB when compared with AB hearts alone. Increase in expression of autophagy related genes could also be observed after hemodynamic unloading in mouse failing hearts. Removal of pressure overload by DB led to 2.58-fold (P<0.05) increase in expression of LC3B when compared to sham and AB mice. Thus, our data strongly suggest that protective effect of enhanced mt biogenesis, fusion/mtDNA repair and removal of damaged mitochondria by mitophagy could play an important role in maintaining mt integrity and function in the adult heart with reverse remodeling.

scholarly journals Use of Natriuretic Peptides to Guide and Monitor Heart Failure Therapy

2012 ◽  
Vol 58 (1) ◽  
pp. 62-71 ◽  
Author(s):  
A Mark Richards ◽  
Richard W Troughton
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Natriuretic Peptides ◽  
Hospital Admissions ◽  
Systolic Heart Failure ◽  
Prognostic Indicators ◽  
Full Spectrum ◽  
Cardiac Natriuretic Peptides ◽  
Design Characteristics ◽  
And Function

Abstract BACKGROUND Plasma B-type cardiac natriuretic peptides reflect cardiac structure and function and have proven roles in assisting in the diagnosis of acute heart failure. They are independent prognostic indicators across the full spectrum of cardiovascular disease. Serial changes in plasma B-type cardiac natriuretic peptides parallel prognosis in chronic heart failure. Beneficial responses to medications and devices used in the treatment of heart failure are associated with decreases in plasma B-type peptide concentrations. This effect has led to the hypothesis that intensified treatment directed at reducing B-peptide concentrations may improve outcomes in heart failure. CONTENT The efficacy of serial measurements of plasma B-type peptides in guiding titration of therapy for chronic heart failure has been the subject of several randomized controlled trials reported in the peer-reviewed literature since 2000. These reports are summarized in this review. Trial design, characteristics of the heart-failure population studied, duration of follow-up, exact end points recorded, and target peptide concentrations pursued all differ somewhat between trials. In addition, in studies in which benefits were seen, the exact mechanisms mediating the improvements in outcome were unclear. However, an overall consistency is emerging that is supported by 2 metaanalyses. SUMMARY In aggregate the existing trial data suggest that adjustment of treatment in chronic heart failure according to serial B-type peptide measurements, used in conjunction with established clinical methods, is likely to reduce cardiac mortality and hospital admissions with heart failure, at least in patients with systolic heart failure who are younger than 75 years and relatively free of comorbidities.

scholarly journals Role of Mitochondria-Cytoskeleton Interactions in the Regulation of Mitochondrial Structure and Function in Cancer Stem Cells

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1691
Author(s):  
Jungmin Kim ◽  
Jae-Ho Cheong
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Energy Requirement ◽  
High Energy ◽  
Structure And Function ◽  
Mitochondrial Morphology ◽  
Voltage Dependent Anion Channel ◽  
Mesenchymal Transition ◽  
Mitochondrial Structure ◽  
And Function

Despite the promise of cancer medicine, major challenges currently confronting the treatment of cancer patients include chemoresistance and recurrence. The existence of subpopulations of cancer cells, known as cancer stem cells (CSCs), contributes to the failure of cancer therapies and is associated with poor clinical outcomes. Of note, one of the recently characterized features of CSCs is augmented mitochondrial function. The cytoskeleton network is essential in regulating mitochondrial morphology and rearrangement, which are inextricably linked to its functions, such as oxidative phosphorylation (OXPHOS). The interaction between the cytoskeleton and mitochondria can enable CSCs to adapt to challenging conditions, such as a lack of energy sources, and to maintain their stemness. Cytoskeleton-mediated mitochondrial trafficking and relocating to the high energy requirement region are crucial steps in epithelial-to-mesenchymal transition (EMT). In addition, the cytoskeleton itself interplays with and blocks the voltage-dependent anion channel (VDAC) to directly regulate bioenergetics. In this review, we describe the regulation of cellular bioenergetics in CSCs, focusing on the cytoskeleton-mediated dynamic control of mitochondrial structure and function.

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