scholarly journals Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts

2021 ◽  
Vol 2 ◽  
Author(s):  
Yuxin Chu ◽  
Cheng Zhang ◽  
Min Xie
Keyword(s):  
Heart Failure ◽  
Energy Metabolism ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Ketone Bodies ◽  
Ischemia Reperfusion ◽  
Alternative Fuel ◽  
Diabetic Patients ◽  
Signaling Molecule ◽  
Beneficial Effects

One of the characteristics of the failing human heart is a significant alteration in its energy metabolism. Recently, a ketone body, β-hydroxybutyrate (β-OHB) has been implicated in the failing heart’s energy metabolism as an alternative “fuel source.” Utilization of β-OHB in the failing heart increases, and this serves as a “fuel switch” that has been demonstrated to become an adaptive response to stress during the heart failure progression in both diabetic and non-diabetic patients. In addition to serving as an alternative “fuel,” β-OHB represents a signaling molecule that acts as an endogenous histone deacetylase (HDAC) inhibitor. It can increase histone acetylation or lysine acetylation of other signaling molecules. β-OHB has been shown to decrease the production of reactive oxygen species and activate autophagy. Moreover, β-OHB works as an NLR family pyrin domain-containing protein 3 (Nlrp3) inflammasome inhibitor and reduces Nlrp3-mediated inflammatory responses. It has also been reported that β-OHB plays a role in transcriptional or post-translational regulations of various genes’ expression. Increasing β-OHB levels prior to ischemia/reperfusion injury results in a reduced infarct size in rodents, likely due to the signaling function of β-OHB in addition to its role in providing energy. Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to exert strong beneficial effects on the cardiovascular system. They are also capable of increasing the production of β-OHB, which may partially explain their clinical efficacy. Despite all of the beneficial effects of β-OHB, some studies have shown detrimental effects of long-term exposure to β-OHB. Furthermore, not all means of increasing β-OHB levels in the heart are equally effective in treating heart failure. The best timing and therapeutic strategies for the delivery of β-OHB to treat heart disease are unknown and yet to be determined. In this review, we focus on the crucial role of ketone bodies, particularly β-OHB, as both an energy source and a signaling molecule in the stressed heart and the overall therapeutic potential of this compound for cardiovascular diseases.

scholarly journals The Cardioprotective Effects of Hydrogen Sulfide in Heart Diseases: From Molecular Mechanisms to Therapeutic Potential

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Yaqi Shen ◽  
Zhuqing Shen ◽  
Shanshan Luo ◽  
Wei Guo ◽  
Yi Zhun Zhu
Keyword(s):  
Hydrogen Sulfide ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Cardiac Diseases ◽  
Mammalian Tissues ◽  
Antioxidative Action

Hydrogen sulfide (H2S) is now recognized as a third gaseous mediator along with nitric oxide (NO) and carbon monoxide (CO), though it was originally considered as a malodorous and toxic gas. H2S is produced endogenously from cysteine by three enzymes in mammalian tissues. An increasing body of evidence suggests the involvement of H2S in different physiological and pathological processes. Recent studies have shown that H2S has the potential to protect the heart against myocardial infarction, arrhythmia, hypertrophy, fibrosis, ischemia-reperfusion injury, and heart failure. Some mechanisms, such as antioxidative action, preservation of mitochondrial function, reduction of apoptosis, anti-inflammatory responses, angiogenic actions, regulation of ion channel, and interaction with NO, could be responsible for the cardioprotective effect of H2S. Although several mechanisms have been identified, there is a need for further research to identify the specific molecular mechanism of cardioprotection in different cardiac diseases. Therefore, insight into the molecular mechanisms underlying H2S action in the heart may promote the understanding of pathophysiology of cardiac diseases and lead to new therapeutic targets based on modulation of H2S production.

scholarly journals Agrin Promotes Coordinated Therapeutic Processes Leading to Improved Cardiac Repair in Pigs

Circulation ◽  
2020 ◽  
Vol 142 (9) ◽  
pp. 868-881 ◽  
Author(s):  
Andrea Baehr ◽  
Kfir Baruch Umansky ◽  
Elad Bassat ◽  
Victoria Jurisch ◽  
Katharina Klett ◽  
...  
Keyword(s):  
Heart Failure ◽  
Single Dose ◽  
Matrix Protein ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Heart Function ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Extracellular Matrix Protein ◽  
Number Of Patients

Background: Ischemic heart diseases are leading causes of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a large number of patients with MI develop chronic heart failure over time. We previously reported that a fragment of the extracellular matrix protein agrin promotes cardiac regeneration after MI in adult mice. Methods: To test the therapeutic potential of agrin in a preclinical porcine model, we performed ischemia–reperfusion injuries using balloon occlusion for 60 minutes followed by a 3-, 7-, or 28-day reperfusion period. Results: We demonstrated that local (antegrade) delivery of recombinant human agrin to the infarcted pig heart can target the affected regions in an efficient and clinically relevant manner. A single dose of recombinant human agrin improved heart function, infarct size, fibrosis, and adverse remodeling parameters 28 days after MI. Short-term MI experiments along with complementary murine studies revealed myocardial protection, improved angiogenesis, inflammatory suppression, and cell cycle reentry as agrin’s mechanisms of action. Conclusions: A single dose of agrin is capable of reducing ischemia–reperfusion injury and improving heart function, demonstrating that agrin could serve as a therapy for patients with acute MI and potentially heart failure.

scholarly journals Exercise training, energy metabolism, and heart failureThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 336-339 ◽  
Author(s):  
Renée Ventura-Clapier
Keyword(s):  
Heart Failure ◽  
Energy Metabolism ◽  
Exercise Training ◽  
Endurance Training ◽  
Cell Function ◽  
Peer Review Process ◽  
The Body ◽  
Industrialized Countries ◽  
Beneficial Effects ◽  
Intracellular Energy Transfer

Energy metabolism is at the crossroad of cell function and dysfunction. Cardiac and skeletal muscle cells, the energy metabolism of which is high, fluctuating, and adaptable to the special needs of the body, have developed sophisticated strategies for synthesizing, transferring, and utilizing energy in accordance with the needs of the body. Adaptation to endurance training mainly involves energetic remodelling in skeletal muscles, but less is known for the cardiac muscle. Alterations in energy metabolism participate in many pathophysiological processes, among which is heart failure. Because endurance training improves symptoms and quality of life and decreases mortality rate and hospitalization, it is increasingly recognized as a beneficial practice for heart failure patients. The mechanisms involved in the beneficial effects of exercise training are far from being understood. Proper evaluation of these mechanisms is thus a major health issue for populations living in industrialized countries. This review mainly focuses on oxidative metabolism and intracellular energy transfer in muscles and the heart, their alterations in heart failure, and the effects of endurance exercise training.

scholarly journals Therapeutic Potential of Novel Twin Compounds Containing Tetramethylpyrazine and Carnitine Substructures in Experimental Ischemic Stroke

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Ziying Wang ◽  
Zhuanli Zhou ◽  
Xinbing Wei ◽  
Mingwei Wang ◽  
Bi-Ou Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Ischemia Reperfusion ◽  
The Novel ◽  
Neuroprotective Effects ◽  
Chemical Structures ◽  
Cerebral Ischemia Reperfusion Injury ◽  
Blood Brain Barrier Integrity

Although studies have seen dramatic advances in the understanding of the pathogenesis of stroke such as oxidative stress, inflammation, excitotoxicity, calcium overload and apoptosis, the delivery of stroke therapies is still a great challenge. In this study, we designed and synthesized a series of novel twin compounds containing tetramethylpyrazine and carnitine substructures and explored their therapeutic potential and mechanism in stroke-related neuronal injury. We first screened the neuroprotective effects of candidate compounds and found that among the tested compounds, LR134 and LR143 exhibited significant neuroprotection as evidenced by reducing cerebral infarct and edema, improving neurological function as well as blood-brain barrier integrity in rats after cerebral ischemia/reperfusion injury. We further demonstrated that the neuroprotective effects of compounds LR134 and LR143 were associated with the reduced inflammatory responses and NADPH oxidase- (NOX2-) mediated oxidative stress and the protection of mitochondria accompanied by the improvement of energy supply. In summary, this study provides direct evidence showing that the novel twin compounds containing tetramethylpyrazine and carnitine substructures have neuroprotective effects with multiple therapeutic targets, suggesting that modulation of these chemical structures may be an innovative therapeutic strategy for treating patients with stroke.

Potential beneficial as well as detrimental effects of chronic treatment with lisinopril and (or) spironolactone on isolated hearts following low-flow ischemia in normal and infarcted rats

2003 ◽  
Vol 81 (9) ◽  
pp. 864-872 ◽  
Author(s):  
Annie Rochetaing ◽  
Catherine Chapon ◽  
Laurent Marescaux ◽  
Anne Le Bouil ◽  
Alain Furber ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ventricular Tachycardia ◽  
Ace Inhibitors ◽  
Ace Inhibitor ◽  
Ischemia Reperfusion ◽  
Reactive Hyperemia ◽  
Low Flow ◽  
Beneficial Effects ◽  
Rat Hearts ◽  
Contractile Recovery

This study was designed to demonstrate potential beneficial as well as detrimental effects of lisinopril and spironolactone given in combination. In patients with congestive heart failure or myocardial infarction, the use of angiotensin-converting enzyme (ACE) inhibitors may inhibit aldosterone production. Spironolactone, a specific aldo sterone receptor antagonist may exert other independent and additive effects to those of ACE inhibitors. Given the consequences of aldosterone on ischemic hearts, we evaluated the protective effects of spironolactone or lisinopril and combined spironolactone–lisinopril therapy during low-flow ischemia and reperfusion in isolated rat hearts. Normal and infarcted (left coronary artery ligature) male Wistar rats were submitted to chronic action of drugs (0.8 mg·kg–1·day–1 for lisinopril and 8 or 50 mg·kg–1·day–1 for spironolactone) for 1 month. Hearts were rapidly excised and perfused (constant pressure) for a 40-min period of stabilization followed by a 25-min period of global low-flow ischemia and a 30-min reperfusion. In normal rats, spironolactone decreased ischemic and reperfusion contracture, reduced ventricular tachycardia, suppressed action-potential duration dispersion, and increased reactive hyperemia leading to an improvement of contractile recovery. Lisinopril also decreased ventricular tachycardia and action-potential duration dispersion concomitantly with increased reactive hyperemia and better contractile recovery. These beneficial effects of the drugs were lost when the two treatments were combined (lisinopril and 50 mg·kg–1·day–1 spironolactone), despite a synergistic effect on plasmatic K+ and Mg2+. However, an interaction between the ACE inhibitor and spironolactone potentiating the effects of either drug alone was observed with a lower dose of spironolactone (lisinopril and 8 mg·kg–1·day–1 spironolactone). Similar beneficial effects have been noted in infarcted rat hearts on reactive hyperemia, ventricular tachycardia, and contractile recovery with the combined treatment and for both spironolactone concentrations (8 or 50 mg). Chronic spironolactone treatment produces similar beneficial effects to ACE inhibitor treatment on normal rat hearts during an ischemia-reperfusion protocol. Synergistic effects have been observed with the combined therapy when a lower dose of spironolactone was utilized in normal and infarcted rats. However, in the case of a high dose of spironolactone, the two effective drugs seem to cancel each other but only in normal rats.Key words: spironolactone, ACE inhibitors, ischemia–reperfusion, ventricular arrhythmia, action potentials, coronary flow, congestive heart failure.

scholarly journals Potential Implications of Quercetin and its Derivatives in Cardioprotection

2020 ◽  
Vol 21 (5) ◽  
pp. 1585 ◽  
Author(s):  
Kristina Ferenczyova ◽  
Barbora Kalocayova ◽  
Monika Bartekova
Keyword(s):  
Therapeutic Potential ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Experimental Models ◽  
Cardiac Effects ◽  
Beneficial Effects ◽  
Positive Effects ◽  
Number Of Patients ◽  
Wide Range

Quercetin (QCT) is a natural polyphenolic compound enriched in human food, mainly in vegetables, fruits and berries. QCT and its main derivatives, such as rhamnetin, rutin, hyperoside, etc., have been documented to possess many beneficial effects in the human body including their positive effects in the cardiovascular system. However, clinical implications of QCT and its derivatives are still rare. In the current paper we provide a complex picture of the most recent knowledge on the effects of QCT and its derivatives in different types of cardiac injury, mainly in ischemia-reperfusion (I/R) injury of the heart, but also in other pathologies such as anthracycline-induced cardiotoxicity or oxidative stress-induced cardiac injury, documented in in vitro and ex vivo, as well as in in vivo experimental models of cardiac injury. Moreover, we focus on cardiac effects of QCT in presence of metabolic comorbidities in addition to cardiovascular disease (CVD). Finally, we provide a short summary of clinical studies focused on cardiac effects of QCT. In general, it seems that QCT and its metabolites exert strong cardioprotective effects in a wide range of experimental models of cardiac injury, likely via their antioxidant, anti-inflammatory and molecular pathways-modulating properties; however, ageing and presence of lifestyle-related comorbidities may confound their beneficial effects in heart disease. On the other hand, due to very limited number of clinical trials focused on cardiac effects of QCT and its derivatives, clinical data are inconclusive. Thus, additional well-designed human studies including a high enough number of patients testing different concentrations of QCT are needed to reveal real therapeutic potential of QCT in CVD. Finally, several negative or controversial effects of QCT in the heart have been reported, and this should be also taken into consideration in QCT-based approaches aimed to treat CVD in humans.

Beneficial effects of exercise training in heart failure are lost in male diabetic rats

2017 ◽  
Vol 123 (6) ◽  
pp. 1579-1591
Author(s):  
Dalila Boudia ◽  
Valérie Domergue ◽  
Philippe Mateo ◽  
Loubina Fazal ◽  
Mathilde Prud’homme ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Cardiac Function ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Coronary Artery Ligation ◽  
Standard Diet ◽  
Beneficial Effects ◽  
Patients With Heart Failure

Exercise training has been demonstrated to have beneficial effects in patients with heart failure (HF) or diabetes. However, it is unknown whether diabetic patients with HF will benefit from exercise training. Male Wistar rats were fed either a standard (Sham, n = 53) or high-fat, high-sucrose diet ( n = 66) for 6 mo. After 2 mo of diet, the rats were already diabetic. Rats were then randomly subjected to either myocardial infarction by coronary artery ligation (MI) or sham operation. Two months later, heart failure was documented by echocardiography and animals were randomly subjected to exercise training with treadmill for an additional 8 wk or remained sedentary. At the end, rats were euthanized and tissues were assayed by RT-PCR, immunoblotting, spectrophotometry, and immunohistology. MI induced a similar decrease in ejection fraction in diabetic and lean animals but a higher premature mortality in the diabetic group. Exercise for 8 wk resulted in a higher working power developed by MI animals with diabetes and improved glycaemia but not ejection fraction or pathological phenotype. In contrast, exercise improved the ejection fraction and increased adaptive hypertrophy after MI in the lean group. Trained diabetic rats with MI were nevertheless able to develop cardiomyocyte hypertrophy but without angiogenic responses. Exercise improved stress markers and cardiac energy metabolism in lean but not diabetic-MI rats. Hence, following HF, the benefits of exercise training on cardiac function are blunted in diabetic animals. In conclusion, exercise training only improved the myocardial profile of infarcted lean rats fed the standard diet. NEW & NOTEWORTHY Exercise training is beneficial in patients with heart failure (HF) or diabetes. However, less is known of the possible benefit of exercise training for HF patients with diabetes. Using a rat model where both diabetes and MI had been induced, we showed that 2 mo after MI, 8 wk of exercise training failed to improve cardiac function and metabolism in diabetic animals in contrast to lean animals.

Abstract 82: Regulation Of Frataxin By HIF-1 In The Ischemic Diabetic Heart

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Raj H Amin ◽  
Abdullah AlAsmari ◽  
Gayani Nanayakkari ◽  
John Quindry ◽  
Shavanthi Mouli ◽  
...  
Keyword(s):  
Heart Failure ◽  
Insulin Signalling ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Hypoxia Inducible Factor ◽  
Diabetic Heart ◽  
Diabetic Patients ◽  
Hypoxic Injury ◽  
Infarction Size

Background: Diabetes is at epidemic proportions, with the major form of fatality due to congestive heart failure triggered by myocardial infarction (MI). The impaired insulin signalling in the diabetic heart leads to myocardial energy dysregulation that compromises the cardioprotective mechanism against ischemic injury. Therefore understanding how mitochondrial energetics is altered in the diabetic ischemic heart would greatly advance the knowledge base for improving outcomes from heart failure in diabetic patients. Methods/Findings: We observed that db/db mice (leptin deficient, type 2 diabetic mice) have increased infarction size (>30%) compared to wild type mice after ischemia/reperfusion (IR) injury by TTC stain. We also found that activity of Hypoxia inducible factor-1 (HIF1) is involved in the cardioprotective response to ischemia, is impaired in db/db hearts. HIF1 is known to transcriptionally regulate genes involved in myocardial energetics. We recently found that HIF1 transcriptionally regulates the mitochondrial protein frataxin (Fxn) in cardiomyocytes as determined by luciferase assays (>3 fold). In vitro studies indicate that hypoxic conditions increase Fxn protein expression in cardiomyocytes as determined by western analysis (2 fold). Fxn plays an important role in the Fe-S cluster biogenesis required for aconitase, succinate dehydrogenase and complexes in the mitochondria. Interestingly, we observed decreased expression of Fxn in the ischemic diabetic heart. Conclusion: we postulate that attenuated HIF1-Fxn signalling in ischemic diabetic heart leads to abnormally enlarged infarction size in response to IR. The decline in HIF-1 activity in response to hypoxia was further validated in cardiomyocytes cultured in high glucose media. The significance for Fxn against hypoxic injury was confirmed by utilizing overexpressed Fxn cardiomyocytes via MTT, ATP and aconitase activity assays. Current and future work: currently we are attempting to identify the HIF response element (HRE) in Fxn promoter to further validate the transcriptional activity of HIF1. In addition, we are completing the IR surgeries on HIF1 KO mice to address the cardioprotective nature of HIF1-Fxn signalling against MI.

Abstract 422: Small Molecule and Activated Fibroblast Targeting of the Gβγ-GRK2 Interface After Myocardial Ischemia Attenuates Heart Failure Progression

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Joshua G Travers ◽  
Fadia A Kamal ◽  
Inigo Valiente-Alandi ◽  
Michelle L Nieman ◽  
Michelle A Sargent ◽  
...  
Keyword(s):  
Heart Failure ◽  
Myocardial Ischemia ◽  
G Protein ◽  
Small Molecule ◽  
Therapeutic Potential ◽  
Interstitial Fibrosis ◽  
Cardiac Fibroblasts ◽  
Ischemia Reperfusion ◽  
Heart Failure Progression ◽  
Activated Fibroblasts

Cardiac fibroblasts are a critical cell population responsible for myocardial extracellular matrix homeostasis. Upon injury or pathologic stimulation, these cells transform to an activated myofibroblast state and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation, a hallmark of heart failure, induces pathologic signaling through G protein βγ subunits and their interaction with G protein-coupled receptor kinase 2 (GRK2). We hypothesized that Gβγ-GRK2 inhibition/ablation after myocardial injury would attenuate pathologic myofibroblast activation and cardiac remodeling. The therapeutic potential of small molecule Gβγ-GRK2 inhibition alone or in combination with activated fibroblast- or myocyte-specific GRK2 ablation, each initiated after myocardial ischemia/reperfusion (I/R) injury, was investigated to evaluate possible salutary effects on post-I/R fibroblast activation, pathologic remodeling and cardiac function. Small molecule Gβγ-GRK2 inhibition initiated one week post-injury was cardioprotective in the I/R model of chronic heart failure, including preservation of cardiac contractility and reduction in cardiac fibrotic remodeling. Systemic small molecule Gβγ-GRK2 inhibition initiated one week post-I/R in cardiomyocyte-restricted GRK2 ablated mice (also post-I/R) demonstrated additional cardioprotection, suggesting a potential protective role beyond the cardiomyocyte. Inducible ablation of GRK2 in activated fibroblasts (i.e. myofibroblasts) post-I/R injury demonstrated significant functional cardioprotection with reduced myofibroblast transformation and fibrosis. Systemic small molecule Gβγ-GRK2 inhibition initiated one week post-I/R provided little to no further protection in mice with ablation of GRK2 in activated fibroblasts alone. Finally, Gβγ-GRK2 inhibition significantly attenuated activation characteristics of failing human cardiac fibroblasts isolated from end stage heart failure patients. These findings suggest a potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression.

scholarly journals Cardiac and skeletal muscle energy metabolism in heart failure: beneficial effects of voluntary activity

2002 ◽  
Vol 56 (2) ◽  
pp. 260-268 ◽  
Author(s):  
E DESOUSA ◽  
P LECHENE ◽  
D FORTIN ◽  
B NGUESSAN ◽  
S BELMADANI ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Voluntary Activity ◽  
Beneficial Effects ◽  
Muscle Energy ◽  
Muscle Energy Metabolism
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