scholarly journals Emerging Role of Mitophagy in the Heart: Therapeutic Potentials to Modulate Mitophagy in Cardiac Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yi Luan ◽  
Ying Luan ◽  
Qi Feng ◽  
Xing Chen ◽  
Kai-Di Ren ◽  
...  
Keyword(s):  
Heart Failure ◽  
Energy Supply ◽  
Heart Function ◽  
High Energy ◽  
Normal Function ◽  
Cardiac Diseases ◽  
Normal Heart ◽  
Beneficial Effects ◽  
Physiological Processes

The normal function of the mitochondria is crucial for most tissues especially for those that demand a high energy supply. Emerging evidence has pointed out that healthy mitochondrial function is closely associated with normal heart function. When these processes fail to repair the damaged mitochondria, cells initiate a removal process referred to as mitophagy to clear away defective mitochondria. In cardiomyocytes, mitophagy is closely associated with metabolic activity, cell differentiation, apoptosis, and other physiological processes involved in major phenotypic alterations. Mitophagy alterations may contribute to detrimental or beneficial effects in a multitude of cardiac diseases, indicating potential clinical insights after a close understanding of the mechanisms. Here, we discuss the current opinions of mitophagy in the progression of cardiac diseases, such as ischemic heart disease, diabetic cardiomyopathy, cardiac hypertrophy, heart failure, and arrhythmia, and focus on the key molecules and related pathways involved in the regulation of mitophagy. We also discuss recently reported approaches targeting mitophagy in the therapy of cardiac diseases.

scholarly journals Physical Exercise and Cardiac Repair: The Potential Role of Nitric Oxide in Boosting Stem Cell Regenerative Biology

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1002
Author(s):  
Fabiola Marino ◽  
Mariangela Scalise ◽  
Eleonora Cianflone ◽  
Luca Salerno ◽  
Donato Cappetta ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Stem Cell ◽  
Physical Exercise ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Heart Function ◽  
Stem Cell Biology ◽  
Myocardial Repair ◽  
Beneficial Effects

Over the years strong evidence has been accumulated showing that aerobic physical exercise exerts beneficial effects on the prevention and reduction of cardiovascular risk. Exercise in healthy subjects fosters physiological remodeling of the adult heart. Concurrently, physical training can significantly slow-down or even reverse the maladaptive pathologic cardiac remodeling in cardiac diseases, improving heart function. The underlying cellular and molecular mechanisms of the beneficial effects of physical exercise on the heart are still a subject of intensive study. Aerobic activity increases cardiovascular nitric oxide (NO) released mainly through nitric oxidase synthase 3 activity, promoting endothelium-dependent vasodilation, reducing vascular resistance, and lowering blood pressure. On the reverse, an imbalance between increasing free radical production and decreased NO generation characterizes pathologic remodeling, which has been termed the “nitroso-redox imbalance”. Besides these classical evidence on the role of NO in cardiac physiology and pathology, accumulating data show that NO regulate different aspects of stem cell biology, including survival, proliferation, migration, differentiation, and secretion of pro-regenerative factors. Concurrently, it has been shown that physical exercise generates physiological remodeling while antagonizes pathologic remodeling also by fostering cardiac regeneration, including new cardiomyocyte formation. This review is therefore focused on the possible link between physical exercise, NO, and stem cell biology in the cardiac regenerative/reparative response to physiological or pathological load. Cellular and molecular mechanisms that generate an exercise-induced cardioprotective phenotype are discussed in regards with myocardial repair and regeneration. Aerobic training can benefit cells implicated in cardiovascular homeostasis and response to damage by NO-mediated pathways that protect stem cells in the hostile environment, enhance their activation and differentiation and, in turn, translate to more efficient myocardial tissue regeneration. Moreover, stem cell preconditioning by and/or local potentiation of NO signaling can be envisioned as promising approaches to improve the post-transplantation stem cell survival and the efficacy of cardiac stem cell therapy.

scholarly journals Pannexins and Connexins: Their Relevance for Oocyte Developmental Competence

2021 ◽  
Vol 22 (11) ◽  
pp. 5918
Author(s):  
Paweł Kordowitzki ◽  
Gabriela Sokołowska ◽  
Marta Wasielak-Politowska ◽  
Agnieszka Skowronska ◽  
Mariusz T. Skowronski
Keyword(s):  
Assisted Reproductive Technologies ◽  
Mammalian Species ◽  
Atp Release ◽  
Reproductive Technologies ◽  
High Energy ◽  
Developmental Competence ◽  
Physiological Processes ◽  
Protein Group ◽  
Multicellular Organisms

The oocyte is the major determinant of embryo developmental competence in all mammalian species. Although fundamental advances have been generated in the field of reproductive medicine and assisted reproductive technologies in the past three decades, researchers and clinicians are still trying to elucidate molecular factors and pathways, which could be pivotal for the oocyte’s developmental competence. The cell-to-cell and cell-to-matrix communications are crucial not only for oocytes but also for multicellular organisms in general. This latter mentioned communication is among others possibly due to the Connexin and Pannexin families of large-pore forming channels. Pannexins belong to a protein group of ATP-release channels, therefore of high importance for the oocyte due to its requirements of high energy supply. An increasing body of studies on Pannexins provided evidence that these channels not only play a role during physiological processes of an oocyte but also during pathological circumstances which could lead to the development of diseases or infertility. Connexins are proteins that form membrane channels and gap-junctions, and more precisely, these proteins enable the exchange of some ions and molecules, and therefore they do play a fundamental role in the communication between the oocyte and accompanying cells. Herein, the role of Pannexins and Connexins for the processes of oogenesis, folliculogenesis, oocyte maturation and fertilization will be discussed and, at the end of this review, Pannexin and Connexin related pathologies and their impact on the developmental competence of oocytes will be provided.

scholarly journals The Diverse Roles of TNNI3K in Cardiac Disease and Potential for Treatment

2021 ◽  
Vol 22 (12) ◽  
pp. 6422
Author(s):  
Caroline Pham ◽  
Noelia Muñoz-Martín ◽  
Elisabeth M. Lodder
Keyword(s):  
Cardiac Disease ◽  
Genetic Variants ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Regeneration ◽  
Cardiac Diseases ◽  
Supraventricular Arrhythmias ◽  
Clinical Perspective ◽  
Physiological Processes

In the two decades since the discovery of TNNI3K it has been implicated in multiple cardiac phenotypes and physiological processes. TNNI3K is an understudied kinase, which is mainly expressed in the heart. Human genetic variants in TNNI3K are associated with supraventricular arrhythmias, conduction disease, and cardiomyopathy. Furthermore, studies in mice implicate the gene in cardiac hypertrophy, cardiac regeneration, and recovery after ischemia/reperfusion injury. Several new papers on TNNI3K have been published since the last overview, broadening the clinical perspective of TNNI3K variants and our understanding of the underlying molecular biology. We here provide an overview of the role of TNNI3K in cardiomyopathy and arrhythmia covering both a clinical perspective and basic science advancements. In addition, we review the potential of TNNI3K as a target for clinical treatments in different cardiac diseases.

scholarly journals AMPK: a therapeutic target of heart failure—not only metabolism regulation

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Xuan Li ◽  
Jia Liu ◽  
Qingguo Lu ◽  
Di Ren ◽  
Xiaodong Sun ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Function ◽  
Critical Role ◽  
Ampk Activation ◽  
Atp Production ◽  
Metabolism Regulation ◽  
Physiological Processes ◽  
Clinical Drugs ◽  
Serious Disease ◽  
Amp Activated Protein Kinase

Abstract Heart failure (HF) is a serious disease with high mortality. The incidence of this disease has continued to increase over the past decade. All cardiovascular diseases causing dysfunction of various physiological processes can result in HF. AMP-activated protein kinase (AMPK), an energy sensor, has pleiotropic cardioprotective effects and plays a critical role in the progression of HF. In this review, we highlight that AMPK can not only improve the energy supply in the failing heart by promoting ATP production, but can also regulate several important physiological processes to restore heart function. In addition, we discuss some aspects of some potential clinical drugs which have effects on AMPK activation and may have value in treating HF. More studies, especially clinical trials, should be done to evaluate manipulation of AMPK activation as a potential means of treating HF.

Role of KATP Channels in Beneficial Effects of Exercise in Ischemic Heart Failure

2015 ◽  
Vol 47 (12) ◽  
pp. 2504-2512 ◽  
Author(s):  
JASENKA KRALJEVIC ◽  
MORTEN ANDRE HØYDAL ◽  
MARKO LJUBKOVIC ◽  
JOSE BIANCO NASCIMENTO MOREIRA ◽  
KARI JØRGENSEN ◽  
...  
Keyword(s):  
Heart Failure ◽  
Katp Channels ◽  
Ischemic Heart ◽  
Ischemic Heart Failure ◽  
Beneficial Effects

scholarly journals Impact of circadian time of dosing on cardiac-autonomous effects of glucocorticoids

2021 ◽  
Author(s):  
Michelle Wintzinger ◽  
Manoj Panta ◽  
Karen Miz ◽  
Ashok D.P. Pragasam ◽  
Michelle Sargent ◽  
...  
Keyword(s):  
Heart Failure ◽  
Energy Demand ◽  
Heart Function ◽  
Daily Intake ◽  
Metabolic Stress ◽  
Single Pulse ◽  
High Energy ◽  
Dark Phase ◽  
Light Phase ◽  
Circadian Time

Bioenergetic capacity is critical to adapt the high energy demand of the heart to circadian oscillations and diseased states. Glucocorticoids regulate the circadian cycle of energy metabolism, but little is known about how circadian timing of exogenous glucocorticoid dosing directly regulates cardiac bioenergetics through the primary receptor of these drugs, the glucocorticoid receptor (GR). While chronic once-daily intake of glucocorticoids promotes metabolic stress and heart failure, we recently discovered that intermittent once-weekly dosing of exogenous glucocorticoids promoted muscle metabolism and heart function in dystrophic mice. However, the effects of glucocorticoid intermittence on heart failure beyond muscular dystrophy remain unknown. Here we investigated the extent to which circadian time of dosing regulates the cardiac-autonomous effects of the glucocorticoid prednisone in conditions of single pulse or chronic intermittent dosing. In WT mice, we found that prednisone improved cardiac content of NAD+ and ATP with light-phase dosing (ZT0), while the effects were blocked by dark-phase dosing (ZT12). The effects on mitochondrial function were cardiomyocyte-autonomous, as shown by inducible cardiomyocyte-restricted GR ablation, and depended on an intact activating clock complex, as shown by hearts from BMAL1-KO mice. Conjugating time-of-dosing with chronic intermittence, we found that once-weekly light-phase prednisone improved metabolism and function in heart after myocardial injury. Our study identifies cardiac-autonomous mechanisms through which circadian time and chronic intermittence reconvert glucocorticoid drugs to bioenergetic boosters for the heart.

scholarly journals Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

2021 ◽  
Vol 54 (1) ◽  
Author(s):  
Manuel Ramos-Kuri ◽  
Sri Harika Meka ◽  
Fabio Salamanca-Buentello ◽  
Roger J. Hajjar ◽  
Larissa Lipskaia ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Mapk Pathway ◽  
Therapeutic Targets ◽  
Cardiac Diseases ◽  
Ras Genes ◽  
Septal Defects ◽  
Pathological Cardiac Hypertrophy

Abstract The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The present review provides an update on the role of the H-, K- and N-Ras genes and their related pathways in cardiac diseases. We focus on cardiac hypertrophy and heart failure, where Ras has been studied the most. We also review other cardiac diseases, like genetic disorders related to Ras. The scope of the review extends from fundamental concepts to therapeutic applications. Although the three Ras genes have a nearly identical primary structure, there are important functional differences between them: H-Ras mainly regulates cardiomyocyte size, whereas K-Ras regulates cardiomyocyte proliferation. N-Ras is the least studied in cardiac cells and is less associated to cardiac defects. Clinically, oncogenic H-Ras causes Costello syndrome and facio-cutaneous-skeletal syndromes with hypertrophic cardiomyopathy and arrhythmias. On the other hand, oncogenic K-Ras and alterations of other genes of the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, like Raf, cause Noonan syndrome and cardio-facio-cutaneous syndromes characterized by cardiac hypertrophy and septal defects. We further review the modulation by Ras of key signaling pathways in the cardiomyocyte, including: (i) the classical Ras-Raf-MAPK pathway, which leads to a more physiological form of cardiac hypertrophy; as well as other pathways associated with pathological cardiac hypertrophy, like (ii) The SAPK (stress activated protein kinase) pathways p38 and JNK; and (iii) The alternative pathway Raf-Calcineurin-Nuclear Factor of Activated T cells (NFAT). Genetic alterations of Ras isoforms or of genes in the Ras-MAPK pathway result in Ras-opathies, conditions frequently associated with cardiac hypertrophy or septal defects among other cardiac diseases. Several studies underline the potential role of H- and K-Ras as a hinge between physiological and pathological cardiac hypertrophy, and as potential therapeutic targets in cardiac hypertrophy and failure. Graphic abstract

scholarly journals Vitamin C and Cardiovascular Disease: An Update

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1227
Author(s):  
Marco B. Morelli ◽  
Jessica Gambardella ◽  
Vanessa Castellanos ◽  
Valentina Trimarco ◽  
Gaetano Santulli
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Vitamin C ◽  
Antioxidant Properties ◽  
Cerebrovascular Diseases ◽  
Preclinical Studies ◽  
Cardiovascular Disorders ◽  
Beneficial Effects ◽  
Pathological Conditions

The potential beneficial effects of the antioxidant properties of vitamin C have been investigated in a number of pathological conditions. In this review, we assess both clinical and preclinical studies evaluating the role of vitamin C in cardiac and vascular disorders, including coronary heart disease, heart failure, hypertension, and cerebrovascular diseases. Pitfalls and controversies in investigations on vitamin C and cardiovascular disorders are also discussed.

P1616L-2-hydroxyglutarate dehydrogenase (L2HGDH) is a novel target for heart failure due to pressure overload

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Remes ◽  
L Ding ◽  
B Kamlage ◽  
U E E Rennefahrt ◽  
P Ternes ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ribosomal Protein ◽  
Mitochondrial Membrane ◽  
Heart Function ◽  
Mtor Signaling ◽  
Heart Weight ◽  
Macrophage Migration ◽  
Mrna Levels ◽  
Ribosomal Protein S6

Abstract Background We have found L-2-hydroxyglutarate dehydrogenase (L2HGDH) to be downregulated in the myocardium of mice subjected to transverse aortic constriction (TAC). L2HGDH is an important regulator of mitochondrial bioenergetics by catalyzing the conversion of L-2-hydroxyglutarate (L2-HG) to α-ketoglutarate. However, the connection between L2-HG accumulation and heart failure is not yet understood. Purpose Purpose of our study was to investigate the role of increased L2-HG levels in heart failure and the potential role of L2HGDH overexpression as therapeutic strategy. Methods For in vitro studies, primary rat neonatal cardiomyocytes (NRVCMs) were incubated with L2-HG. L2HGDH was overexpressed using adeno-associated virus (AAV) 6 vectors. Mitochondrial membrane potential was measured using TMRE (tetramethylrhodamine ethyl ester) dye. Mitochondrial reactive oxygen species production was monitored using MitoSOX. We further determined activation of fetal gene program by real time qPCR and macrophage migration using RAW 264.7 cells and transwell inserts. mTOR activation was analyzed by Western blot with antibodies against phosphorylated mTOR and ribosomal protein S6. AAV9 expressing L2HGDH or luciferase was injected in C57BL/6N mice two weeks prior to TAC and heart function was monitored by echocardiography for 6 weeks. Results L2-HG acts as a pro-hypertrophic stimulus in NRVCMs as shown by upregulation of a fetal gene expression pattern and an increase in cardiomyocyte cross-sectional area upon L2-HG treatment. Furthermore, mRNA levels of macrophage chemoattractant protein 1 were increased in L2-HG treated cells, which correlated with enhanced macrophage migration towards supernatant of L2-HG treated NRVCMs. Furthermore, we could confirm that L2-HG augmented mTOR signaling by affecting the phosphorylation status of ribosomal protein S6. AAV-mediated L2HGDH overexpression in NRVCMs led to a significant 2.1-fold decrease in the accumulation of ROS production. Moreover, we found an inhibition of endothelin-1 induced mitochondrial membrane depolarization in AAV6-L2HGDH transduced cells. Pretreatment of mice with AAV9-L2HGDH prior to TAC resulted in significantly reduced heart weight to tibia length ratios (HW/TL) and cardiomyocyte area. Importantly, heart function was notably improved in mice receiving gene therapy (ejection fraction, EF: 36.18±6.63%, fractional shortening, FS: 16.72±4.01%) whereas control animals showed marked decline in myocardial contractility (EF: 20.14±8.24%, FS: 12.66±6.66%). Conclusion L2-HG causes cardiomyocyte dysfunction by activating mTOR signaling pathway, a well-characterized critical inducer of myocyte hypertrophy, and enhancing macrophage migration, leading to establishment of a pro-inflammatory environment in the myocardium. Moreover, our results point out towards a novel preventive approach for cardiac hypertrophy and heart failure by cardiomyocyte-specific L2HGDH overexpression. Acknowledgement/Funding DZHK (Deutsches Zentrum für Herz-Kreislaufforschung)

Impact of stroke on heart function

ESC CardioMed ◽  
2018 ◽  
pp. 954-957
Author(s):  
Christoph Kleinschnitz
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Atrial Fibrillation ◽  
Congestive Heart Failure ◽  
Heart Disease ◽  
Neurological Disease ◽  
Heart Function ◽  
Population Based ◽  
Cardiac Diseases ◽  
Possible Cause

Much emphasis has been placed on the heart as a possible cause of neurological disease. Cardiac diseases, such as atrial fibrillation, valvular heart disease, or congestive heart failure are well-established, important risk factors for ischaemic stroke. Within population-based studies, about 30% of ischaemic strokes are caused by cardiac diseases.

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