Cardiac-Specific Bdh1 Overexpression Ameliorates Oxidative Stress and Cardiac Remodeling in Pressure Overload–Induced Heart Failure

Uchihashi, Motoki; Hoshino, Atsushi; Okawa, Yoshifumi; Ariyoshi, Makoto; Kaimoto, Satoshi; Tateishi, Shuhei; Ono, Kazunori; Yamanaka, Ryoetsu; Hato, Daichi; Fushimura, Yohei; Honda, Susumu; Fukai, Kuniyoshi; Higuchi, Yusuke; Ogata, Toru; Iwai-Kanai, Eri; Matoba, Satoaki

doi:10.1161/circheartfailure.117.004417

Cited by 121 publications

(86 citation statements)

References 29 publications

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“…3, G-I, and 4). Thus, the present model of MI-induced HF did not have upregulated ketone oxidation in the myocardium in contrast to HF models in earlier studies (Schugar et al, 2014;Aubert et al, 2016;Bedi et al, 2016;Diakos et al, 2016;Uchihashi et al, 2017), possibly because the duration of cardiac overload (12 hours vs. 4-8 weeks), severity of HF (post-MI vs. aortic banding model), and/or presence of DM were different. Nevertheless, treatment with empagliflozin increased blood and myocardial bOHB levels by approximately 2-and 10-fold, respectively, and the increased tissue level of bOHB was accompanied by preservation of ATP level after MI.…”

Section: Discussioncontrasting

confidence: 82%

“…On the other hand, ketone oxidation increases to compensate for the decrease in acetyl CoA production in the failing heart (Aubert et al, 2016;Bedi et al, 2016). Recently, it has been reported that cardiac-specific overexpression of BDH1 was protective in mice, while knockout of SCOT was detrimental to HF induced by pressure overload (Schugar et al, 2014;Uchihashi et al, 2017). These results support the notion that promotion of ketone oxidation improves the energy metabolism in failing hearts.…”

Section: Discussionsupporting

confidence: 57%

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Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats

Oshima¹,

Miki²,

Kuno³

et al. 2018

J Pharmacol Exp Ther

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The mechanism by which SGLT2 inhibitors reduce cardiac events in diabetic patients remains unclear. Here, we examined the effects of an SGLT2 inhibitor on the acute survival rate after myocardial infarction (MI) in an animal model of type 2 diabetes mellitus (DM) and the possible involvement of modification of cardiac metabolomes and antioxidative proteins. MI was induced in DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) control rats. Treatment with empagliflozin (10 mg/kg per day, 14 days) before MI reduced blood glucose and increased blood and myocardial b-hydroxybutyrate (bOHB) levels in OLETF. Survival rate at 48 hours after MI was significantly lower in OLETF rats than in LETO rats (40% vs. 84%), and empagliflozin significantly improved the survival rate in OLETF rats to 70%, although the sizes of MI were comparable. Patterns of metabolomes and gene expression in the noninfarcted myocardium of OLETF rats were consistent with increased fatty acid oxidation and decreased glucose oxidation. The patterns were modified by empagliflozin, suggesting both increased glucose oxidation and ketone utilization in OLETF rats. Empagliflozin prevented reduction of ATP level in the noninfarcted myocardium after MI and significantly increased myocardial levels of Sirt3 and superoxide dismutase 2 in OLETF rats. Administration of bOHB partially mimicked the effects of empagliflozin in OLETF rats. The results suggest that empagliflozin prevents DM-induced increase in post-MI mortality, possibly by protective modification of cardiac energy metabolism and antioxidant proteins.

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Section: Discussioncontrasting

confidence: 82%

Section: Discussionsupporting

confidence: 57%

Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats

Oshima¹,

Miki²,

Kuno³

et al. 2018

J Pharmacol Exp Ther

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“…Regardless, the results of the Oxct1 -/and csBDH1 -/mice, together with the observed increase in 3OHB oxidation in the failing heart that occurs in the context of reduced utilization of fatty acids, suggest that ketone bodies are being used as an alternate oxidative fuel in order to maintain adequate ATP generation. This result is further supported by the recent observation that transgenic mice overexpressing BDH1 exhibit less pathologic remodeling in response to TAC (42).…”

Section: Discussionsupporting

confidence: 69%

The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense

et al. 2019

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“…d-β-hydroxybutyrate dehydrogenase I (BDH1) promotes the interconversion of acetoacetate and β-hydroxybutyrate. Cardiac-specific overexpression of BDH1 promotes the expression of antioxidants to diminish ROS levels and reverse oxidative stress-induced DNA injury to attenuate heart failure [139]. Collectively, the physiological level of ketone bodies such as β-hydroxybutyrate protects cells from oxidative stress and prevents the acceleration of cardiac remodeling.…”

Section: Butyrate and Butyrylationmentioning

confidence: 99%

Short-chain fatty acid, acylation and cardiovascular diseases

2020

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Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Metabolic dysfunction is a fundamental core mechanism underlying CVDs. Previous studies generally focused on the roles of long-chain fatty acids (LCFAs) in CVDs. However, a growing body of study has implied that short-chain fatty acids (SCFAs: namely propionate, malonate, butyrate, 2-hydroxyisobutyrate (2-HIBA), β-hydroxybutyrate, crotonate, succinate, and glutarate) and their cognate acylations (propionylation, malonylation, butyrylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, crotonylation, succinylation, and glutarylation) participate in CVDs. Here, we attempt to provide an overview landscape of the metabolic pattern of SCFAs in CVDs. Especially, we would focus on the SCFAs and newly identified acylations and their roles in CVDs, including atherosclerosis, hypertension, and heart failure. Clinical Science (2020) 134 657-676 https://doi.org/10.1042/CS20200128 cofactors in certain protein acylations, such as propionylation [14], malonylation [15], butyrylation [14], 2-hydroxyisobutyrylation [16], β-hydroxybutyrylation [17], crotonylation [18], succinylation [19], and glutarylation [20]. These discoveries give us a deeper understanding of PTM. Among PTMs, protein acetylation is the earliest discovered and most studied. Similar to protein acetylation, various studies have shown that these newly discovered PTMs are also involved in physiological and pathophysiological processes, including cardiovascular homeostasis.Here in this review, we will summarize SCFAs, protein acylations, and their emerging roles in CVDs, including atherosclerosis, hypertension, and heart failure. The metabolic pattern and FAs in CVDsThe heart is an 'omnivore' , using FAs, glucose, lactate, ketone bodies, and amino acids as metabolic substrates [5,6]. The substrates utilized by the embryonic heart are significantly different from those used by the adult heart. The embryonic heart depends primarily on glycolysis as well as lactate oxidation to produce energy [21]. The newborn and adult heart shift toward the remarkable utilization of FAs to meet cardiac energy demand [5,9]. In failing hearts, a decrease in FA oxidation and an increase in glycolysis are critically involved in cardiac dysfunction [22]. As thus, the metabolic pattern is essential for maintaining cardiac and vascular functions.Diabetes, hypertension, and obesity contribute to heart failure syndrome. Accumulating evidence suggests that hypertension, ischemic hearts, and heart failure induce a shift in substrate toward the remarkable utilization of glucose to generate energy. Despite this shift, the FA oxidation remains to make much energy for the diseased heart [23]. Since FAs are the predominant substrates for cardiomyocytes, alterations in FA metabolism have been implicated as causal in cardiac diseases. FAs within cells and in the circulation are critically involved in cardiometabolic diseases. CVDs are closely associated with lifestyle and metabolic status, which affect circul...

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Cardiac-Specific Bdh1 Overexpression Ameliorates Oxidative Stress and Cardiac Remodeling in Pressure Overload–Induced Heart Failure

Abstract: We demonstrated that ketone body oxidation increased in failing hearts, and increased ketone body utilization decreased oxidative stress and protected against heart failure.

Cited by 121 publications

References 29 publications

Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats

Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats

The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense

Short-chain fatty acid, acylation and cardiovascular diseases

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