bims-hafaim 2023-04-16 papers

Issue of 2023–04–16
six papers selected by
Kyle McCommis, Saint Louis University

Front Endocrinol (Lausanne). 2023 ;14 1122125

O-GlcNAcylation-induced GSK-3β activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice.

Mahito Matsuno, Shunichi Yokoe, Takehiro Nagatsuka, Hirofumi Morihara, Kazumasa Moriwaki, Michio Asahi.

O-GlcNAc transferase (OGT) modulates many functions of proteins via O-GlcNAcylation that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to the serine/threonine residues of proteins. However, the role of O-GlcNAcylation in cardiac remodeling and function is not fully understood. To examine the effect of O-GlcNAcylation on pressure overload-induced cardiac hypertrophy and subsequent heart failure, transverse aortic constriction (TAC) surgery was performed in wild type (WT) and Ogt transgenic (Ogt-Tg) mice. Four weeks after TAC (TAC4W), the heart function of Ogt-Tg mice was significantly lower than that of WT mice (reduced fractional shortening and increased ANP levels). The myocardium of left ventricle (LV) in Ogt-Tg mice became much thinner than that in WT mice. Moreover, compared to the heart tissues of WT mice, O-GlcNAcylation of GSK-3β at Ser9 was increased and phosphorylation of GSK-3β at Ser9 was reduced in the heart tissues of Ogt-Tg mice, resulting in its activation and subsequent inactivation of nuclear factor of activated T cell (NFAT) activity. Finally, the thinned LV wall and reduced cardiac function induced by TAC4W in Ogt-Tg mice was reversed by the treatment of a GSK-3β inhibitor, TDZD-8. These results imply that augmented O-GlcNAcylation exacerbates pressure overload-induced heart failure due to a lack of compensatory cardiac hypertrophy via O-GlcNAcylation of GSK-3β, which deprives the phosphorylation site of GSK-3β to constantly inactivate NFAT activity to prevent cardiac hypertrophy. Our findings may provide a new therapeutic strategy for cardiac hypertrophy and subsequent heart failure.

Keywords: GSK-3β; O-GlcNAcylation; heart failure; hypertrophy; transverse aortic constriction (TAC)

DOI: https://doi.org/10.3389/fendo.2023.1122125

Int J Mol Sci. 2023 Apr 06. pii: 6842. [Epub ahead of print]24(7):

Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor Ameliorate Metabolic Disorder and Obesity Induced Cardiomyocyte Injury and Mitochondrial Remodeling.

Shih-Jie Jhuo, Yi-Hsiung Lin, I-Hsin Liu, Tsung-Hsien Lin, Bin-Nan Wu, Kun-Tai Lee, Wen-Ter Lai.

Sodium-glucose transporter 2 inhibitors (SGLT2is) exert significant cardiovascular and heart failure benefits in type 2 diabetes mellitus (DM) patients and can help reduce cardiac arrhythmia incidence in clinical practice. However, its effect on regulating cardiomyocyte mitochondria remain unclear. To evaluate its effect on myocardial mitochondria, C57BL/6J mice were divided into four groups, including: (1) control, (2) high fat diet (HFD)-induced metabolic disorder and obesity (MDO), (3) MDO with empagliflozin (EMPA) treatment, and (4) MDO with glibenclamide (GLI) treatment. All mice were sacrificed after 16 weeks of feeding and the epicardial fat secretome was collected. H9c2 cells were treated with the different secretomes for 18 h. ROS production, Ca2+ distribution, and associated proteins expression in mitochondria were investigated to reveal the underlying mechanisms of SGLT2is on cardiomyocytes. We found that lipotoxicity, mitochondrial ROS production, mitochondrial Ca2+ overload, and the levels of the associated protein, SOD1, were significantly lower in the EMPA group than in the MDO group, accompanied with increased ATP production in the EMPA-treated group. The expression of mfn2, SIRT1, and SERCA were also found to be lower after EMPA-secretome treatment. EMPA-induced epicardial fat secretome in mice preserved a better cardiomyocyte mitochondrial biogenesis function than the MDO group. In addition to reducing ROS production in mitochondria, it also ameliorated mitochondrial Ca2+ overload caused by MDO-secretome. These findings provide evidence and potential mechanisms for the benefit of SGLT2i in heart failure and arrhythmias.

Keywords: SGLT2 inhibitor; calcium overload; empagliflozin; epicardial fat; mitochondria; oxidative stress

DOI: https://doi.org/10.3390/ijms24076842

Circ Res. 2023 Apr 14. 132(8): 1034-1049

Cardiac Metabolism in Heart Failure and Implications for Uremic Cardiomyopathy.

T Dung Nguyen, P Christian Schulze.

Chronic kidney disease is associated with an increased risk for the development and progression of cardiovascular disorders including hypertension, dyslipidemia, and coronary artery disease. Chronic kidney disease may also affect the myocardium through complex systemic changes, resulting in structural remodeling such as hypertrophy and fibrosis, as well as impairments in both diastolic and systolic function. These cardiac changes in the setting of chronic kidney disease define a specific cardiomyopathic phenotype known as uremic cardiomyopathy. Cardiac function is tightly linked to its metabolism, and research over the past 3 decades has revealed significant metabolic remodeling in the myocardium during the development of heart failure. Because the concept of uremic cardiomyopathy has only been recognized in recent years, there are limited data on metabolism in the uremic heart. Nonetheless, recent findings suggest overlapping mechanisms with heart failure. This work reviews key features of metabolic remodeling in the failing heart in the general population and extends this to patients with chronic kidney disease. The knowledge of similarities and differences in cardiac metabolism between heart failure and uremic cardiomyopathy may help identify new targets for mechanistic and therapeutic research on uremic cardiomyopathy.

Keywords: heart failure; metabolism; renal insufficiency, chronic

DOI: https://doi.org/10.1161/CIRCRESAHA.123.321759

JACC Basic Transl Sci. 2023 Mar;8(3): 258-279

Cardiac Transcriptome Remodeling and Impaired Bioenergetics in Single-Ventricle Congenital Heart Disease.

Anastacia M Garcia, Lee S Toni, Carissa A Miyano, Genevieve C Sparagna, Raleigh Jonscher, Elisabeth K Phillips, Anis Karimpour-Fard, Hailey L Chapman, Angela N Baybayon-Grandgeorge, Ashley E Pietra, Emma Selner, Kathryn C Chatfield, Brian L Stauffer, Carmen C Sucharov, Shelley D Miyamoto.

The mechanisms responsible for heart failure in single-ventricle congenital heart disease are unknown. Using explanted heart tissue, we showed that failing single-ventricle hearts have dysregulated metabolic pathways, impaired mitochondrial function, decreased activity of carnitine palmitoyltransferase activity, and altered functioning of the tricarboxylic acid cycle. Interestingly, nonfailing single-ventricle hearts demonstrated an intermediate metabolic phenotype suggesting that they are vulnerable to development of heart failure in the future. Mitochondrial targeted therapies and treatments aimed at normalizing energy generation could represent a novel approach to the treatment or prevention of heart failure in this vulnerable group of patients.

Keywords: cardiac metabolism; cardiometabolic remodeling; heart failure; hypoplastic left heart syndrome; mitochondria; oxidative phosphorylation; single ventricle

DOI: https://doi.org/10.1016/j.jacbts.2022.09.013

Eur J Pharmacol. 2023 Apr 11. pii: S0014-2999(23)00231-5. [Epub ahead of print] 175720

Canagliflozin protects diabetic cardiomyopathy by mitigating fibrosis and preserving the myocardial integrity with improved mitochondrial function.

Deepika Dasari, Srashti Gopal Goyal, Anuhya Penmetsa, Dharmarajan Sriram, Arti Dhar.

Sodium-glucose transport protein 2 (SGLT-2) inhibitors are approved antidiabetic drugs with a beneficial effect on reducing major adverse cardiac events and heart failure hospitalization. Among them, canagliflozin has the least selectivity toward SGLT-2 over the SGLT-1 isoform. Canagliflozin can inhibit SGLT-1 at therapeutic levels; however, the underlying molecular mechanism is not understood. This study aimed to evaluate the effect of canagliflozin on SGLT1 expression in an animal model of diabetic cardiomyopathy (DCM) and its associated effects. In vivo studies were carried out in the most clinically relevant high-fat diet and streptozotocin-induced type-2 diabetes model of diabetic cardiomyopathy, and in vitro studies were performed using cultured rat cardiomyocytes stimulated with high glucose and palmitic acid. DCM was induced in male Wistar rats for 8 weeks with or without 10 mg/kg canagliflozin treatment. At the end of the study, systemic and molecular characteristics were measured using immunofluorescence, quantitative RT‒PCR, immunoblotting, histology, and FACS analysis. SGLT-1 expression was upregulated in DCM hearts and was associated with fibrosis, apoptosis, and hypertrophy. Canagliflozin treatment attenuated these changes. The histological evaluation showed improved myocardial structure, and in vitro results revealed improved mitochondrial quality and biogenesis after canagliflozin treatment. In conclusion, canagliflozin protects the DCM heart by inhibiting myocardial SGLT-1 and associated hypertrophy, fibrosis, and apoptosis. Thus, developing novel pharmacological inhibitors targeting SGLT-1 could be a better strategy for treating DCM and associated cardiovascular complications.

Keywords: Apoptosis; Canagliflozin; Fibrosis; Hypertrophy; NHE-1; Type-2 diabetes

DOI: https://doi.org/10.1016/j.ejphar.2023.175720

Circ Cardiovasc Imaging. 2023 Apr 12. e015298

Cardioprotective Effect of Empagliflozin and Circulating Ketone Bodies During Acute Myocardial Infarction.

Carlos G Santos-Gallego, Juan Antonio Requena-Ibáñez, Belen Picatoste, Brian Fardman, Kiyotake Ishikawa, Renata Mazurek, Michael Pieper, Samantha Sartori, Jorge Rodriguez-Capitán, Valentin Fuster, Juan J Badimon.

BACKGROUND: SGLT2i (sodium-glucose cotransporter-2 inhibitors) improve clinical outcomes in patients with heart failure, but the mechanisms of action are not completely understood. SGLT2i increases circulating levels of ketone bodies, which has been demonstrated to enhance myocardial energetics and induce reverse ventricular remodeling. However, the role of SGLT2i or ketone bodies on myocardial ischemia reperfusion injury remains in the dark. The objective of this study is to investigate the cardioprotective potential of empagliflozin and ketone bodies during acute myocardial infarction (MI).
METHODS: We used a nondiabetic porcine model of ischemia reperfusion using a percutaneous occlusion of proximal left anterior descending artery for 45 minutes. Animals received 1-week pretreatment with either empagliflozin or placebo prior to MI induction. Additionally, a third group received intravenous infusion of the ketone body beta-hydroxybutyrate BOHB (beta-hydroxybutyrate) during the MI induction. Acute effects of the treatments were assessed 4-hour post-MI by cardiac magnetic resonance and histology (thioflavin for area at risk, triphenyltetrazolium chloride staining for MI size). All animals were euthanized immediately postcardiac magnetic resonance, and heart samples were collected.
RESULTS: The area at risk was similar in all groups. Empagliflozin treatment increased BOHB levels. Empagliflozin-treated animals showed significantly higher myocardial salvage, smaller MI size (both by cardiac magnetic resonance and histology), less microvascular obstruction, and improved cardiac function (left ventricle ejection fraction and strain). Furthermore, empagliflozin-treated animals demonstrated reduced biomarkers of cardiomyocyte apoptosis and oxidative stress compared with placebo. The BOHB group showed similar results to the empagliflozin group.
CONCLUSIONS: One-week pretreatment with empagliflozin ameliorates ischemia reperfusion injury, reduces MI size and microvascular obstruction, increases myocardial salvage, preserves left ventricle systolic function, and lowers apoptosis and oxidative stress. Periprocedural intravenous infusion of BOHB during myocardial ischemia also induces cardioprotection, suggesting a role for BOHB availability as an additional mechanism within the wide spectrum of actions of SGLT2i.

Keywords: empagliflozin; glucose; ketone bodies; myocardial infarction; reperfusion

DOI: https://doi.org/10.1161/CIRCIMAGING.123.015298