Targeting Mitochondria-Inflammation Circuit by β-Hydroxybutyrate Mitigates HFpEF

Deng, Yan; Xie, Maodi; Li, Qian; Xu, Xuewen; Ou, Wei; Zhang, Ya-Bing; Xiao, Haitao; Yu, Hai; Zheng, Yue; Liang, Yu; Jiang, Chunling; Chen, Guo; Du, Dan; Zheng, Wen; Wang, Shisheng; Gong, Meng; Chen, Yaohui; Tian, Rong; Li, Tao

doi:10.1161/circresaha.120.317933

Cited by 253 publications

(235 citation statements)

References 40 publications

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“…First, the current data did not address the exact mechanism whereby O-GlcNAcylation activates G6PDH. In our opinion, it could be due to direct activation via O-GlcNAc modification of serine/threonine residues in G6PDH catalytic domain, similar to a recent report about β-OHB-mediated activation of citrate synthase [ 51 ], or indirect regulation such as competitive inhibition of other post-translational modification machinery on G6PDH. More detailed studies, like site-specific mutagenesis, are required to test these possibilities.…”

Section: Discussionsupporting

confidence: 84%

Hypoxic acclimation improves cardiac redox homeostasis and protects heart against ischemia-reperfusion injury through upregulation of O-GlcNAcylation

Liang

Yu³

et al. 2021

Redox Biology

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Ischemia-reperfusion (I/R) injury is detrimental to cardiovascular system. Alteration in glucose metabolism has been recognized as an important adaptive response under hypoxic conditions. However, the biological benefits underlying this metabolic phenotype remain to be elucidated. This study was designed to investigate the impact of hypoxic acclimation (HA) on cardiac I/R injury and the antioxidative mechanism(s). Male adult mice were acclimated in a hypoxic chamber (10% oxygen [O 2 ]) for 8 h/day for 14 days, and then subjected to cardiac I/R injury by ligation of left anterior descending coronary artery for 30 min and reperfusion for 24 h or 7 days. Our results showed that HA attenuated oxidative stress and reduced infarct size in the I/R hearts. This cardioprotective effect is coupled with an elevation of protein O-linked N -acetylglucosamine (O-GlcNAc) modification partially due to inflammatory stimulation. Hyperglycosylation activated glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme in the pentose phosphate pathway, resulting in an upregulation of NADPH/NADP + and GSH/GSSG couples and enhancement of redox homeostasis in the heart. Pharmacological suppression of O-GlcNAcylation totally abolished the influence of HA on the G6PDH activity, redox balance and post-I/R damage in the hearts and cultured cardiomyocytes, whereby augmentation of O-GlcNAcylation further enhanced the benefits, suggesting a central role of O-GlcNAcylation in HA-initiated antioxidative and cardioprotective effects. These findings, therefore, identified HA as a promising anti-I/R strategy for the heart and proposed O-GlcNAc modification of G6PDH as a therapeutic target in ischemic heart disease.

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Section: Discussionsupporting

confidence: 84%

Hypoxic acclimation improves cardiac redox homeostasis and protects heart against ischemia-reperfusion injury through upregulation of O-GlcNAcylation

Liang

Yu³

et al. 2021

Redox Biology

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“…Although β-OHB is an energy substrate, there was no change in ATP production in response to β-OHB treatment (Figure 6e). In contrast to the increased ketone utilization previously reported in end-stage heart failure [22] and HFpEF (heart failure with preserved ejection fraction) [23], the β-OHB treatment did not contribute to cardiomyocyte ATP production under hypoxic conditions, suggesting that the cardiomyocytes did not use ketone bodies as an alternative energy source.…”

Section: β-Ohb Metabolisms Were Obscured Under Hypoxic Conditions In Cardiac Myocytescontrasting

confidence: 87%

“…This observation is obscure because it is contradictory to the alterative ketone utilization observed in advanced-stage heart failure. Previous research has shown that hypertrophied and failing hearts undergo regulatory gene reprogramming to increase the uptake and oxidation of ketone bodies [23,28]. Specifically, the expression of BDH1 and the transporter SLC16A1…”

Section: Discussionmentioning

confidence: 99%

β-Hydroxybutyrate Exacerbates Hypoxic Injury by Inhibiting HIF-1α-Dependent Glycolysis in Cardiomyocytes—Adding Fuel to the Fire?

Dong

Liu

et al. 2021

Preprint

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Purpose: Ketone body oxidation yields more ATP per mole of consumed oxygen than glucose. However, whether an increased ketone body supply in hypoxic cardiomyocytes and ischemic hearts is protective or not remains elusive. The goal of this study is to determine the effect of β-hydroxybutyrate (β-OHB), the main constituent of ketone bodies, on cardiomyocytes under hypoxic conditions and the effects of ketogenic diet (KD) on cardiac function in a myocardial infarction (MI) mouse model. Methods: Adult mouse cardiomyocytes and MI mouse models fed a KD were used to research the effect of β-OHB on cardiac damage. qPCR, western blot analysis and immunofluorescence were used to detect the interaction between β-OHB and glycolysis. Live/dead cell staining and imaging, lactate dehydrogenase, Cell Counting Kit-8 assays, echocardiography and 2,3,5-triphenyltetrazolium chloride staining were performed to evaluate the cardiomyocyte death, cardiac function and infarct sizes. Results: β-OHB level was significantly higher in acute MI patients and MI mice. Treatment with β-OHB exacerbated cardiomyocyte death and decreased glucose absorption and glycolysis under hypoxic conditions. These effects were partially ameliorated by inhibiting hypoxia-inducible factor 1α (HIF-1α) degradation via roxadustat administration in hypoxia-stimulated cardiomyocytes. Furthermore, β-OHB metabolisms were obscured in cardiomyocytes under hypoxic conditions. Additionally, MI mice fed a KD exhibited exacerbated cardiac dysfunction compared with control chow diet (CD)-fed MI mice. Conclusion: Elevated β-OHB levels may be maladaptive to the heart under hypoxic/ischemic conditions. Administration of roxadustat can partially reverse these harmful effects by stabilizing HIF-1α and inducing a metabolic shift toward glycolysis for energy production.

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“…A recent study on HFpEF supported that systemic inflammation may be the association between comorbidity and HF ( 191 ). The IL-1β and IL-18 signaling pathways may be novel drug targets for HFpEF, which are important in the mitochondria-inflammation circuit ( 192 ).…”

Section: Link Between Heart Failure and Comorbiditiesmentioning

confidence: 99%

Metabolism and Chronic Inflammation: The Links Between Chronic Heart Failure and Comorbidities

Zhao

Wang

2021

Front. Cardiovasc. Med.

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Heart failure (HF) patients often suffer from multiple comorbidities, such as diabetes, atrial fibrillation, depression, chronic obstructive pulmonary disease, and chronic kidney disease. The coexistance of comorbidities usually leads to multi morbidity and poor prognosis. Treatments for HF patients with multi morbidity are still an unmet clinical need, and finding an effective therapy strategy is of great value. HF can lead to comorbidity, and in return, comorbidity may promote the progression of HF, creating a vicious cycle. This reciprocal correlation indicates there may be some common causes and biological mechanisms. Metabolism remodeling and chronic inflammation play a vital role in the pathophysiological processes of HF and comorbidities, indicating metabolism and inflammation may be the links between HF and comorbidities. In this review, we comprehensively discuss the major underlying mechanisms and therapeutic implications for comorbidities of HF. We first summarize the potential role of metabolism and inflammation in HF. Then, we give an overview of the linkage between common comorbidities and HF, from the perspective of epidemiological evidence to the underlying metabolism and inflammation mechanisms. Moreover, with the help of bioinformatics, we summarize the shared risk factors, signal pathways, and therapeutic targets between HF and comorbidities. Metabolic syndrome, aging, deleterious lifestyles (sedentary behavior, poor dietary patterns, smoking, etc.), and other risk factors common to HF and comorbidities are all associated with common mechanisms. Impaired mitochondrial biogenesis, autophagy, insulin resistance, and oxidative stress, are among the major mechanisms of both HF and comorbidities. Gene enrichment analysis showed the PI3K/AKT pathway may probably play a central role in multi morbidity. Additionally, drug targets common to HF and several common comorbidities were found by network analysis. Such analysis has already been instrumental in drug repurposing to treat HF and comorbidity. And the result suggests sodium-glucose transporter-2 (SGLT-2) inhibitors, IL-1β inhibitors, and metformin may be promising drugs for repurposing to treat multi morbidity. We propose that targeting the metabolic and inflammatory pathways that are common to HF and comorbidities may provide a promising therapeutic strategy.

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Targeting Mitochondria-Inflammation Circuit by β-Hydroxybutyrate Mitigates HFpEF

Cited by 253 publications

References 40 publications

Hypoxic acclimation improves cardiac redox homeostasis and protects heart against ischemia-reperfusion injury through upregulation of O-GlcNAcylation

Hypoxic acclimation improves cardiac redox homeostasis and protects heart against ischemia-reperfusion injury through upregulation of O-GlcNAcylation

β-Hydroxybutyrate Exacerbates Hypoxic Injury by Inhibiting HIF-1α-Dependent Glycolysis in Cardiomyocytes—Adding Fuel to the Fire?

Metabolism and Chronic Inflammation: The Links Between Chronic Heart Failure and Comorbidities

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