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

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.

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AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease

Clinical Science ◽

10.1042/cs20080066 ◽

2009 ◽

Vol 116 (8) ◽

pp. 607-620 ◽

Cited By ~ 109

Author(s):

Aaron K. F. Wong ◽

Jacqueline Howie ◽

John R. Petrie ◽

Chim C. Lang

Keyword(s):

Protein Kinase ◽

Metabolic Diseases ◽

Elongation Factor ◽

Cardiometabolic Disease ◽

Acid Oxidation ◽

Ampk Activation ◽

Atp Production ◽

Beneficial Effects ◽

Eukaryotic Elongation Factor ◽

Amp Activated Protein Kinase

AMPK (AMP-activated protein kinase) is a heterotrimetric enzyme that is expressed in many tissues, including the heart and vasculature, and plays a central role in the regulation of energy homoeostasis. It is activated in response to stresses that lead to an increase in the cellular AMP/ATP ratio caused either by inhibition of ATP production (i.e. anoxia or ischaemia) or by accelerating ATP consumption (i.e. muscle contraction or fasting). In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. There is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. A principle mode of AMPK activation is phosphorylation by upstream kinases [e.g. LKB1 and CaMK (Ca2+/calmodulin-dependent protein kinase], which leads to direct effects on tissues and phosphorylation of various downstream kinases [e.g. eEF2 (eukaryotic elongation factor 2) kinase and p70 S6 kinase]. These upstream and downstream kinases of AMPK have fundamental roles in glucose metabolism, fatty acid oxidation, protein synthesis and tumour suppression; consequently, they have been implicated in cardiac ischaemia, arrhythmias and hypertrophy. Recent mechanistic studies have shown that AMPK has an important role in the mechanism of action of MF (metformin), TDZs (thiazolinediones) and statins. Increased understanding of the beneficial effects of AMPK activation provides the rationale for targeting AMPK in the development of new therapeutic strategies for cardiometabolic disease.

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/3259963 ◽

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.

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Polyphenol Stilbenes from Fenugreek (Trigonella foenum-graecumL.) Seeds Improve Insulin Sensitivity and Mitochondrial Function in 3T3-L1 Adipocytes

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/7634362 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Gang Li ◽

Guangxiang Luan ◽

Yanfeng He ◽

Fangfang Tie ◽

Zhenhua Wang ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Kinase ◽

Critical Role ◽

Atp Production ◽

Specific Proteins ◽

Signaling Activation ◽

And Function ◽

Amp Activated Protein Kinase ◽

Oil Red O Staining

Fenugreek (Trigonella foenum-graecumL.) is a well-known annual plant that is widely distributed worldwide and has possessed obvious hypoglycemic and hypercholesterolemia characteristics. In our previous study, three polyphenol stilbenes were separated from fenugreek seeds. Here, we investigated the effect of polyphenol stilbenes on adipogenesis and insulin resistance in 3T3-L1 adipocytes. Oil Red O staining and triglyceride assays showed that polyphenol stilbenes differently reduced lipid accumulation by suppressing the expression of adipocyte-specific proteins. In addition, polyphenol stilbenes improved the uptake of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) by promoting the phosphorylation of protein kinase B (AKT) and AMP-activated protein kinase (AMPK). In present studies, it was found that polyphenol stilbenes had the ability to scavenge reactive oxygen species (ROS). Results from adenosine triphosphate (ATP) production and mitochondrial membrane potentials suggested that mitochondria play a critical role in insulin resistance and related signaling activation, such as AKT and AMPK. Rhaponticin, one of the stilbenes from fenugreek, had the strongest activity among the three compoundsin vitro.Future studies will focus on mitochondrial biogenesis and function.

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ANTI-AGING PROTEIN CD9 AFFECTS AGE-RELATED HEART FAILURE

Innovation in Aging ◽

10.1093/geroni/igz038.953 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S255-S255

Author(s):

Sriya T Jonnakuti ◽

Mujib Ullah

Keyword(s):

Heart Failure ◽

Heart Function ◽

Transmembrane Protein ◽

Critical Role ◽

Heart Beat ◽

Term Survival ◽

Paracrine Effects ◽

Aged Mice ◽

Age Related ◽

Increased Risk

Abstract The CD9 is transmembrane protein that plays a critical role in many cellular processes including aging associated cardiac pathologies. The heart function declines in the aged population. Ageing is strongly associated with many age-related conditions such as increased risk of heart failure. If aging can be prevented slowed down or even reversed, heart failure and other signs of aging could be controlled or even cured. It is unknown whether CD9 is cardioprotective. The objective of this study is to investigate whether a decline CD9 levels contributes to aging-related heart failure. Our data shows that CD9-deficient aged mice develop cardiac abnormalities and pathological cardiac hypertrophy, Cardioprotection by CD9 in old mice is followed by the downregulation of SIRT6 in the heart, and CD9 overexpressed exosomes ameliorates cardiac pathologies in treated mice and improves their long-term survival. Additionally, the serum level of CD9 decreased significantly in aged mice. CD9 overexpressed exosomes are cardioprotective and improve cardiac function in aged mice. These exosomes mediate their paracrine effects by attenuating, blood pressure, heart beat, reactive oxygen species and fibrosis. Remarkably, CD9 overexpression reversed fibrosis associated brain natriuretic peptide (BNP), Sirt6, and galectin 3 (Gal-3). These results provide a new perspective on the pathogenesis of cardiomyopathies and open new avenues for treatment of the disease.

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AMP-activated protein kinase protects against anoxia in Drosophila melanogaster

10.1101/162719 ◽

2017 ◽

Author(s):

Justin J. Evans ◽

Chengfeng Xiao ◽

R. Meldrum Robertson

Keyword(s):

Protein Kinase ◽

Fat Body ◽

Ampk Activation ◽

Energy Status ◽

Locomotor Recovery ◽

Atp Production ◽

Production And Consumption ◽

Anoxic Coma ◽

Genetic Targeting ◽

Amp Activated Protein Kinase

AbstractDuring anoxia, proper energy maintenance is essential in order to maintain neural operation. Starvation activates AMP-activated protein kinase (AMPK), an evolutionarily conserved indicator of cellular energy status, in a cascade which modulates ATP production and consumption. We investigated the role of energetic status on anoxia tolerance in Drosophila and discovered that starvation or AMPK activation increases the speed of locomotor recovery from an anoxic coma. Using temporal and spatial genetic targeting we found that AMPK in the fat body contributes to starvation-induced fast locomotor recovery, whereas, under fed conditions, disrupting AMPK in oenocytes prolongs recovery. By evaluating spreading depolarization in the fly brain during anoxia we show that AMPK activation reduces the severity of ionic disruption and prolongs recovery of electrical activity. Further genetic targeting indicates that glial, but not neuronal, AMPK affects locomotor recovery. Together, these findings support a model in which AMPK is neuroprotective in Drosophila.

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Role of angiotensin II in the development of subcellular remodeling in heart failure

Exploration of Medicine ◽

10.37349/emed.2021.00054 ◽

2021 ◽

pp. 352-371

Author(s):

Sukhwinder K. Bhullar ◽

Anureet K. Shah ◽

Naranjan S. Dhalla

Keyword(s):

Heart Failure ◽

Angiotensin Ii ◽

Heart Function ◽

Critical Role ◽

Pressure Overload ◽

Renin Angiotensin System ◽

Volume Overload ◽

Experimental Models ◽

Ang Ii ◽

Beneficial Effects

The development of heart failure under various pathological conditions such as myocardial infarction (MI), hypertension and diabetes are accompanied by adverse cardiac remodeling and cardiac dysfunction. Since heart function is mainly determined by coordinated activities of different subcellular organelles including sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils for regulating the intracellular concentration of Ca2+, it has been suggested that the occurrence of heart failure is a consequence of subcellular remodeling, metabolic alterations and Ca2+-handling abnormalities in cardiomyocytes. Because of the elevated plasma levels of angiotensin II (ANG II) due to activation of the renin-angiotensin system (RAS) in heart failure, we have evaluated the effectiveness of treatments with angiotensin converting enzyme (ACE) inhibitors and ANG II type 1 receptor (AT1R) antagonists in different experimental models of heart failure. Attenuation of marked alterations in subcellular activities, protein content and gene expression were associated with improvement in cardiac function in MI-induced heart failure by treatment with enalapril (an ACE inhibitor) or losartan (an AT1R antagonist). Similar beneficial effects of ANG II blockade on subcellular remodeling and cardiac performance were also observed in failing hearts due to pressure overload, volume overload or chronic diabetes. Treatments with enalapril and losartan were seen to reduce the degree of RAS activation as well as the level of oxidative stress in failing hearts. These observations provide evidence which further substantiate to support the view that activation of RAS and high level of plasma ANG II play a critical role in inducing subcellular defects and cardiac dys-function during the progression of heart failure.

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Hypoxia Induces Expression and Activation of AMPK in Rat Dental Pulp Cells

Journal of Dental Research ◽

10.1177/154405910708600919 ◽

2007 ◽

Vol 86 (9) ◽

pp. 903-907 ◽

Cited By ~ 21

Author(s):

Y. Fukuyama ◽

K. Ohta ◽

R. Okoshi ◽

M. Suehara ◽

H. Kizaki ◽

...

Keyword(s):

Cell Proliferation ◽

Dental Pulp ◽

Hypoxia Inducible Factor ◽

Ampk Activation ◽

Dental Pulp Cells ◽

Atp Production ◽

Pulp Cells ◽

Subunit Isoforms ◽

Amp Activated Protein Kinase ◽

The Relationship

AMP-activated protein kinase (AMPK) is a stress-responsive enzyme involved in cell adaptation to an energy crisis. We hypothesized that hypoxia suppresses oxidative phosphorylation and ATP production, resulting in AMPK activation to protect cells. We investigated the effects of hypoxia on cell proliferation, the expression of AMPK and hypoxia-inducible factor 1α (HIF-1α), the activation of AMPK, and the relationship between AMPK and HIF-1α expression in rat dental pulp RPC-C2A cells. AMPK in the cells was composed of catalytic α1, and regulatory β1 and γ1 subunit isoforms. Cell proliferation was initially suppressed under hypoxia, but it increased thereafter, together with an increase in the expression of AMPK and HIF-1α, and the activation of AMPK. Down-regulation of AMPKα1 by siRNA inhibited cell proliferation under both normoxia and hypoxia, revealing that AMPK induction and activation were required for cell proliferation, although HIF-1α expression under hypoxia was not affected.

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Overexpression of Pygo2 Increases Differentiation of Human Umbilical Cord Mesenchymal Stem Cells into Cardiomyocyte-like Cells

Current Molecular Medicine ◽

10.2174/1566524019666191017150416 ◽

2020 ◽

Vol 20 (4) ◽

pp. 318-324 ◽

Cited By ~ 3

Author(s):

Lei Yang ◽

Shuoji Zhu ◽

Yongqing Li ◽

Jian Zhuang ◽

Jimei Chen ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Heart Function ◽

Critical Role ◽

Human Umbilical Cord ◽

Stem Cell Markers ◽

Quantitative Real Time Pcr ◽

Qrt Pcr

Background: Our previous studies have shown that Pygo (Pygopus) in Drosophila plays a critical role in adult heart function that is likely conserved in mammals. However, its role in the differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) into cardiomyocytes remains unknown. Objective: To investigate the role of pygo2 in the differentiation of hUC-MSCs into cardiomyocytes. Methods: Third passage hUC-MSCs were divided into two groups: a p+ group infected with the GV492-pygo2 virus and a p− group infected with the GV492 virus. After infection and 3 or 21 days of incubation, Quantitative real-time PCR (qRT-PCR) was performed to detect pluripotency markers, including OCT-4 and SOX2. Nkx2.5, Gata-4 and cTnT were detected by immunofluorescence at 7, 14 and 21 days post-infection, respectively. Expression of cardiac-related genes—including Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin—were analyzed by qRT-PCR following transfection with the virus at one, two and three weeks. Results : After three days of incubation, there were no significant changes in the expression of the pluripotency stem cell markers OCT-4 and SOX2 in the p+ group hUC-MSCs relative to controls (OCT-4: 1.03 ± 0.096 VS 1, P > 0.05, SOX2: 1.071 ± 0.189 VS 1, P > 0.05); however, after 21 days, significant decreases were observed (OCT-4: 0.164 ± 0.098 VS 1, P < 0.01, SOX2: 0.209 ± 0.109 VS 1, P < 0.001). Seven days following incubation, expression of mesoderm specialisation markers, such as Nkx2.5, Gata-4, MEF2c and KDR, were increased; at 14 days following incubation, expression of cardiac genes, such as Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin, were significantly upregulated in the p+ group relative to the p− group (P < 0.05). Taken together, these findings suggest that overexpression of pygo2 results in more hUCMSCs gradually differentiating into cardiomyocyte-like cells. Conclusion: We are the first to show that overexpression of pygo2 significantly enhances the expression of cardiac-genic genes, including Nkx2.5 and Gata-4, and promotes the differentiation of hUC-MSCs into cardiomyocyte-like cells.

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PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22158298 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8298

Author(s):

Hugo Christian Monroy-Ramirez ◽

Marina Galicia-Moreno ◽

Ana Sandoval-Rodriguez ◽

Alejandra Meza-Rios ◽

Arturo Santos ◽

...

Keyword(s):

Liver Diseases ◽

Metabolic Regulation ◽

Structural Changes ◽

Critical Role ◽

The Body ◽

Molecular Characteristics ◽

Signal Pathways ◽

Virus Infections ◽

Physiological Processes ◽

Hepatic Level

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.

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Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽

10.3390/antiox10060931 ◽

2021 ◽

Vol 10 (6) ◽

pp. 931

Author(s):

Anureet K. Shah ◽

Sukhwinder K. Bhullar ◽

Vijayan Elimban ◽

Naranjan S. Dhalla

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cardiac Remodeling ◽

Cardiac Dysfunction ◽

Critical Role ◽

Pressure Overload ◽

Hypertrophied Heart ◽

Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

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