bims-hafaim 2022-07-10 papers

Issue of 2022–07–10
six papers selected by
Kyle McCommis, Saint Louis University

Diabetes Obes Metab. 2022 Jul 08.

The SGLT2 inhibitor ertugliflozin modifies the signature of cardiac substrate metabolism and reduces cardiac mTOR-signaling, endoplasmic reticulum stress and apoptosis.

Julia Moellmann, Pascal A Mann, Ben A Kappel, Florian Kahles, Barbara M Klinkhammer, Peter Boor, Rafael Kramann, Bart Ghesquiere, Corinna Lebherz, Nikolaus Marx, Michael Lehrke.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces heart failure (HF) hospitalization in patients with and without diabetes. The underlying mechanisms remain incompletely understood but might relate to the induction of a fasting-like state with low blood glucose and insulin levels and increased ketone body concentrations. This study aimed to investigate cardiac signaling pathways connecting substrate utilization with left ventricular remodeling in a murine pressure overload model.
METHODS AND RESULTS: Cardiac hypertrophy was induced by transverse aortic constriction (TAC) surgery in 20-week-old C57BL/6J mice treated with or without the SGLT2 inhibitor ertugliflozin (225 mg/kg chow diet) for 10 weeks. Ertugliflozin improved left ventricular function and reduced myocardial fibrosis. This occurred simultaneously with a fasting-like response characterized by improved glucose tolerance and increased ketone body concentrations. While cardiac insulin signaling was reduced in response to SGLT2 inhibition, AMP-activated protein kinase (AMPK)-signaling was increased with induction of the fatty acid transporter cluster of differentiation 36 (CD36) and phosphorylation of acetyl-CoA carboxylase (ACC). Further, enzymes responsible for ketone body catabolism (β-hydroxybutyrate dehydrogenase (BDH1), succinyl-CoA:3-oxoacid-CoA transferase (SCOT) and acetyl-CoA acetyltransferase (ACAT) 1) were induced by SGLT2 inhibition. Ertugliflozin led to more cardiac abundance of fatty acids, tricarboxylic acid (TCA) cycle metabolites and adenosine triphosphate (ATP). Downstream mechanistic target of rapamycin (mTOR) pathway, relevant for protein synthesis, cardiac hypertrophy and adverse cardiac remodeling was reduced by SGLT2 inhibition with alleviation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) providing a potential mechanism for abundant reduced left ventricular apoptosis and fibrosis.
CONCLUSION: SGLT2 inhibition reduced left ventricular fibrosis in a murine model of cardiac hypertrophy. Mechanistically, this was associated with reduced cardiac insulin- and increased AMPK-signaling as a potential mechanism for less cardiac mTOR-activation with alleviation of downstream ER stress, UPR and apoptosis. This article is protected by copyright. All rights reserved.

Keywords: SGTL2 inhibitors; ertugliflozin; fasting-like state; heart failure; mTOR; substrate metabolism

DOI: https://doi.org/10.1111/dom.14814

Eur Heart J Cardiovasc Imaging. 2022 Jul 05. pii: jeac121. [Epub ahead of print]

Magnetic resonance imaging of cardiac metabolism in heart failure: how far have we come?

Salva R Yurista, Robert A Eder, Deborah H Kwon, Christian T Farrar, Yi Fen Yen, W H Wilson Tang, Christopher T Nguyen.

As one of the highest energy consumer organs in the body, the heart requires tremendous amount of adenosine triphosphate (ATP) to maintain its continuous mechanical work. Fatty acids, glucose, and ketone bodies are the primary fuel source of the heart to generate ATP with perturbations in ATP generation possibly leading to contractile dysfunction. Cardiac metabolic imaging with magnetic resonance imaging (MRI) plays a crucial role in understanding the dynamic metabolic changes occurring in the failing heart, where the cardiac metabolism is deranged. Also, targeting and quantifying metabolic changes in vivo noninvasively is a promising approach to facilitate diagnosis, determine prognosis, and evaluate therapeutic response. Here, we summarize novel MRI techniques used for detailed investigation of cardiac metabolism in heart failure including magnetic resonance spectroscopy (MRS), hyperpolarized MRS, and chemical exchange saturation transfer based on evidence from preclinical and clinical studies and to discuss the potential clinical application in heart failure.

Keywords: cardiac metabolism; heart failure; hyperpolarized MRS; magnetic resonance imaging; magnetic resonance spectroscopy

DOI: https://doi.org/10.1093/ehjci/jeac121

Cell Calcium. 2022 Jun 22. pii: S0143-4160(22)00091-4. [Epub ahead of print]105 102618

Altered composition of the mitochondrial Ca2+uniporter in the failing human heart.

Melanie Paillard, Kai-Ting Huang, David Weaver, Jonathan P Lambert, John W Elrod, György Hajnóczky.

Heart failure (HF) is a leading cause of hospitalization and mortality worldwide. Yet, there is still limited knowledge on the underlying molecular mechanisms, because human tissue for research is scarce, and data obtained in animal models is not directly applicable to humans. Thus, studies of human heart specimen are of particular relevance. Mitochondrial Ca2+ handling is an emerging topic in HF progression because its regulation is central to the energy supply of the heart contractions as well as to avoiding mitochondrial Ca2+ overload and the ensuing cell death induction. Notably, animal studies have already linked impaired mitochondrial Ca2+ transport to the initiation/progression of HF. Mitochondrial Ca2+ uptake is mediated by the Ca2+uniporter (mtCU) that consists of the MCU pore under tight control by the Ca2+-sensing MICU1 and MICU2. The MICU1/MCU protein ratio has been validated as a predictor of the mitochondrial Ca2+ uptake phenotype. We here determined for the first time the protein composition of the mtCU in the human heart. The two regulators MICU1 and MICU2, were elevated in the failing human heart versus non-failing controls, while the MCU density was unchanged. Furthermore, the MICU1/MCU ratio was significantly elevated in the failing human hearts, suggesting altered gating of the MCU by MICU1 and MICU2. Based on a small cohort of patients, the decrease in the cardiac contractile function (ejection fraction) seems to correlate with the increase in MICU1/MCU ratio. Our findings therefore indicate a possible role for adaptive/maladaptive changes in the mtCU composition in the initiation/progression of human HF in humans and point to a potential therapeutic target at the level of the MICU1-dependent regulation of the mtCU.

Keywords: HFrEF; Heart failure; Human cardiac biopsy; MICU1; MICU2; Mitochondrial Ca2+ signaling; Mitochondrial calcium uniporter; cardiomyopathy

DOI: https://doi.org/10.1016/j.ceca.2022.102618

Open Med (Wars). 2022 ;17(1): 365-374

Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway.

Feifei Zhang, Litian Liu, Yuetao Xie, Jiaqi Wang, Xuefeng Chen, Shihang Zheng, Yingxiao Li, Yi Dang.

Metabolic remodeling contributes to the pathological process of heart failure (HF). We explored the effects of cardiac contractility modulation (CCM) on myocardial metabolic remodeling in the rabbit model with HF. The HF in rabbit model was established by pressure uploading and then CCM was applied. We evaluated the cardiac structure and function by echocardiography, serum BNP level, and hematoxylin and eosin and Masson's trichrome staining. We detected the accumulation of glycogen and lipid droplets in myocardial tissues by periodic acid-Schiff and Oil Red O staining. Then, we measured the contents of glucose, free fatty acid (FFA), lactic acid, pyruvate, and adenosine triphosphate (ATP) levels in myocardial tissues by corresponding kits and the expression levels of key factors related to myocardial substrate uptake and utilization by western blotting were analyzed. CCM significantly restored the cardiac structure and function in the rabbit model with HF. CCM therapy further decreased the accumulation of glycogen and lipid droplets. Furthermore, CCM reduced the contents of FFA, glucose, and lactic acid, and increased pyruvate and ATP levels in HF tissues. The protein expression levels related to myocardial substrate uptake and utilization were markedly improved with CCM treatment by further activating adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor-α signaling pathways.

Keywords: cardiac contractility modulation; heart failure; metabolic remodeling

DOI: https://doi.org/10.1515/med-2022-0415

Int J Mol Sci. 2022 Jun 29. pii: 7255. [Epub ahead of print]23(13):

Chronic Hyperglycaemia Inhibits Tricarboxylic Acid Cycle in Rat Cardiomyoblasts Overexpressing Glucose Transporter Type 4.

Bernd Stratmann, Britta Eggers, Yvonne Mattern, Tayana Silva de Carvalho, Katrin Marcus, Diethelm Tschoepe.

An oversupply of nutrients with a loss of metabolic flexibility and subsequent cardiac dysfunction are hallmarks of diabetic cardiomyopathy. Even if excess substrate is offered, the heart suffers energy depletion as metabolic fluxes are diminished. To study the effects of a high glucose supply, a stably glucose transporter type 4 (GLUT4)-overexpressing cell line presenting an onset of diabetic cardiomyopathy-like phenotype was established. Long-term hyperglycaemia effects were analysed. Rat cardiomyoblasts overexpressing GLUT4 (H9C2KE2) were cultured under normo- and hyperglycaemic conditions for long-term. Expression profiles of several proteins were compared to non-transfected H9C2 cells (H9C2) using RT-qPCR, proteomics-based analysis, or Western blotting. GLUT4 surface analysis, glucose uptake, and cell morphology changes as well as apoptosis/necrosis measurements were performed using flow cytometry. Additionally, brain natriuretic peptide (BNP) levels, reactive oxygen species (ROS) formation, glucose consumption, and lactate production were quantified. Long-term hyperglycaemia in H9C2KE2 cells induced increased GLUT4 presence on the cell surface and was associated with exaggerated glucose influx and lactate production. On the metabolic level, hyperglycaemia affected the tricarboxylic acid (TCA) cycle with accumulation of fumarate. This was associated with increased BNP-levels, oxidative stress, and lower antioxidant response, resulting in pronounced apoptosis and necrosis. Chronic glucose overload in cardiomyoblasts induced by GLUT4 overexpression and hyperglycaemia resulted in metabolically stimulated proteome profile changes and metabolic alterations on the TCA level.

Keywords: TCA cycle; apoptosis; diabetic cardiomyopathy; fumarate; metabolic starvation

DOI: https://doi.org/10.3390/ijms23137255

Oxid Med Cell Longev. 2022 ;2022 9196232

The Role of Mitochondria in Metabolic Syndrome-Associated Cardiomyopathy.

Jiayu Li, Jingye Li, Yijun Chen, Wenyu Hu, Xuhe Gong, Hui Qiu, Hui Chen, Yanguo Xin, Hongwei Li.

With the rapid development of society, the incidence of metabolic syndrome (MS) is increasing rapidly. Evidence indicated that patients diagnosed with MS usually suffered from cardiomyopathy, called metabolic syndrome-associated cardiomyopathy (MSC). The clinical characteristics of MSC included cardiac hypertrophy and diastolic dysfunction, followed by heart failure. Despite many studies on this topic, the detailed mechanisms are not clear yet. As the center of cellular metabolism, mitochondria are crucial for maintaining heart function, while mitochondria dysfunction plays a vital role through mechanisms such as mitochondrial energy deprivation, calcium disorder, and ROS (reactive oxygen species) imbalance during the development of MSC. Accordingly, in this review, we will summarize the characteristics of MSC and especially focus on the mechanisms related to mitochondria. In addition, we will update new therapeutic strategies in this field.

DOI: https://doi.org/10.1155/2022/9196232