The effects of the ketone body β-hydroxybutyrate on isolated rat ventricular myocyte excitation-contraction coupling

Klos, Matthew; Morgenstern, Sherry; Hicks, Kayla; Suresh, Shreyas; Devaney, Eric J.

doi:10.1016/j.abb.2018.11.027

Cited by 23 publications

(12 citation statements)

References 42 publications

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“…Some studies have indicated that β-OHB exhibits beneficial effects in the cardiac system under pathological conditions and can, for example, be used as an alternative fuel in the human failing heart. 43 Moreover, this compound improves cardiac cell excitation-contraction coupling during hypoxia 44 and prevents myocardial damage after coronary occlusion in animal model. 45 In this study, we provided evidence and mechanistic explanations from cultured cells, animal models, and clinical samples to show that long-term KD-induced β-OHB accumulation was detrimental to heart health by promoting cardiac fibrosis (Fig.…”

Section: Discussionmentioning

confidence: 99%

Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis

Tao

Cao

et al. 2021

Sig Transduct Target Ther

122

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In addition to their use in relieving the symptoms of various diseases, ketogenic diets (KDs) have also been adopted by healthy individuals to prevent being overweight. Herein, we reported that prolonged KD exposure induced cardiac fibrosis. In rats, KD or frequent deep fasting decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis. Mechanistically, increased levels of the ketone body β-hydroxybutyrate (β-OHB), an HDAC2 inhibitor, promoted histone acetylation of the Sirt7 promoter and activated Sirt7 transcription. This in turn inhibited the transcription of mitochondrial ribosome-encoding genes and mitochondrial biogenesis, leading to cardiomyocyte apoptosis and cardiac fibrosis. Exogenous β-OHB administration mimicked the effects of a KD in rats. Notably, increased β-OHB levels and SIRT7 expression, decreased mitochondrial biogenesis, and increased cardiac fibrosis were detected in human atrial fibrillation heart tissues. Our results highlighted the unknown detrimental effects of KDs and provided insights into strategies for preventing cardiac fibrosis in patients for whom KDs are medically necessary.

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Section: Discussionmentioning

confidence: 99%

Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis

Tao

Cao

et al. 2021

Sig Transduct Target Ther

122

View full text Add to dashboard Cite

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“…β-Hydroxybutyrate is the primary ketone body produced by the body during ketosis. β-Hydroxybutyrate improves cardiomyocyte excitation-contraction coupling, protects the cells against hypoxic stress and represses cardiomyocyte senescence (45). Cardiomyocyte-specific deficiency of ketone body metabolism by knocking out of succinyl-CoA:3oxoacid CoA transferase (SCOT) promotes mitochondria stress and cell senescence to accelerate pathological remodeling (46).…”

Section: The Regulation Of Metabolism Dysfunction On Cardiomyocyte Sementioning

confidence: 99%

Cardiomyocyte Senescence and Cellular Communications Within Myocardial Microenvironments

2020

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Cardiovascular diseases have become the leading cause of human death. Aging is an independent risk factor for cardiovascular diseases. Cardiac aging is associated with maladaptation of cellular metabolism, dysfunction (or senescence) of cardiomyocytes, a decrease in angiogenesis, and an increase in tissue scarring (fibrosis). These events eventually lead to cardiac remodeling and failure. Senescent cardiomyocytes show the hallmarks of DNA damage, endoplasmic reticulum stress, mitochondria dysfunction, contractile dysfunction, hypertrophic growth, and senescence-associated secreting phenotype (SASP). Metabolism within cardiomyocytes is essential not only to fuel the pump function of the heart but also to maintain the functional homeostasis and participate in the senescence of cardiomyocytes. The senescence of cardiomyocyte is also regulated by the non-myocytes (endothelial cells, fibroblasts, and immune cells) in the local microenvironment. On the other hand, the senescent cardiomyocytes alter their phenotypes and subsequently affect the non-myocytes in the local microenvironment and contribute to cardiac aging and pathological remodeling. In this review, we first summarized the hallmarks of the senescence of cardiomyocytes. Then, we discussed the metabolic switch within senescent cardiomyocytes and provided a discussion of the cellular communications between dysfunctional cardiomyocytes and non-myocytes in the local microenvironment. We also addressed the functions of metabolic regulators within non-myocytes in modulating myocardial microenvironment. Finally, we pointed out some interesting and important questions that are needed to be addressed by further studies.

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“…In addition to acting as an HDAC inhibitor, Nlrp3 inflammasome inhibitor, and GPR ligand, ketone bodies have other roles that are likely to impact the cardiovascular system. As low as 0.5 mM β-OHB can improve cardiac cell excitationcontraction coupling under hypoxia, providing evidence that β-OHB can exert cardioprotective benefits under stress (Klos et al, 2019). β-OHB can also reduce oxidative stress and induce anti-aging effects through binding to hnRNP A1 to upregulate Oct4 expression at the concentration of 4 mM in the vascular system (Han et al, 2018).…”

Section: Other Non-oxidative Roles Of β-Ohbmentioning

confidence: 99%

Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts

2021

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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.

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The effects of the ketone body β-hydroxybutyrate on isolated rat ventricular myocyte excitation-contraction coupling

Cited by 23 publications

References 42 publications

Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis

Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis

Cardiomyocyte Senescence and Cellular Communications Within Myocardial Microenvironments

Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts

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