bims-hafaim 2022-10-09 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022–10–09
five papers selected by
Kyle McCommis, Saint Louis University

Functional remodelling of perinuclear mitochondria alters nucleoplasmic Ca2+ signalling in heart failure.
Effects of altered cellular ultrastructure on energy metabolism in diabetic cardiomyopathy: an in silico study.
Succinyl-CoA-based energy metabolism dysfunction in chronic heart failure.
Ketogenic diet modulates cardiac metabolic dysregulation in streptozocin-induced diabetic rats.
Dapagliflozin Inhibits Ventricular Remodeling in Heart Failure Rats by Activating Autophagy through AMPK/mTOR Pathway.

Philos Trans R Soc Lond B Biol Sci. 2022 Nov 21. 377(1864): 20210320

Functional remodelling of perinuclear mitochondria alters nucleoplasmic Ca2+ signalling in heart failure.

Julia Voglhuber, Michael Holzer, Snježana Radulović, Phung N Thai, Natasa Djalinac, Ingrid Matzer, Markus Wallner, Heiko Bugger, Andreas Zirlik, Gerd Leitinger, Elena N Dedkova, Donald M Bers, Senka Ljubojevic-Holzer.

  Mitochondrial dysfunction in cardiomyocytes is a hallmark of heart failure development. Although initial studies recognized the importance of different mitochondrial subpopulations, there is a striking lack of direct comparison of intrafibrillar (IF) versus perinuclear (PN) mitochondria during the development of HF. Here, we use multiple approaches to examine the morphology and functional properties of IF versus PN mitochondria in pressure overload-induced cardiac remodelling in mice, and in non-failing and failing human cardiomyocytes. We demonstrate that PN mitochondria from failing cardiomyocytes are more susceptible to depolarization of mitochondrial membrane potential, reactive oxygen species generation and impairment in Ca2+ uptake compared with IF mitochondria at baseline and under physiological stress protocol. We also demonstrate, for the first time to our knowledge, that under normal conditions PN mitochondrial Ca2+ uptake shapes nucleoplasmic Ca2+ transients (CaTs) and limits nucleoplasmic Ca2+ loading. The loss of PN mitochondrial Ca2+ buffering capacity translates into increased nucleoplasmic CaTs and may explain disproportionate rise in nucleoplasmic [Ca2+] in failing cardiomyocytes at increased stimulation frequencies. Therefore, a previously unidentified benefit of restoring the mitochondrial Ca2+ uptake may be normalization of nuclear Ca2+ signalling and alleviation of altered excitation-transcription, which could be an important therapeutic approach to prevent adverse cardiac remodelling. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.

Keywords:  heart failure; nuclear calcium; perinuclear mitochondria; remodelling; transverse aortic constriction

DOI:  https://doi.org/10.1098/rstb.2021.0320
Philos Trans R Soc Lond B Biol Sci. 2022 Nov 21. 377(1864): 20210323

Effects of altered cellular ultrastructure on energy metabolism in diabetic cardiomyopathy: an in silico study.

Shouryadipta Ghosh, Giovanni Guglielmi, Ioannis Orfanidis, Fabian Spill, Anthony Hickey, Eric Hanssen, Vijay Rajagopal.

  Diabetic cardiomyopathy is a leading cause of heart failure in diabetes. At the cellular level, diabetic cardiomyopathy leads to altered mitochondrial energy metabolism and cardiomyocyte ultrastructure. We combined electron microscopy (EM) and computational modelling to understand the impact of diabetes-induced ultrastructural changes on cardiac bioenergetics. We collected transverse micrographs of multiple control and type I diabetic rat cardiomyocytes using EM. Micrographs were converted to finite-element meshes, and bioenergetics was simulated over them using a biophysical model. The simulations also incorporated depressed mitochondrial capacity for oxidative phosphorylation (OXPHOS) and creatine kinase (CK) reactions to simulate diabetes-induced mitochondrial dysfunction. Analysis of micrographs revealed a 14% decline in mitochondrial area fraction in diabetic cardiomyocytes, and an irregular arrangement of mitochondria and myofibrils. Simulations predicted that this irregular arrangement, coupled with the depressed activity of mitochondrial CK enzymes, leads to large spatial variation in adenosine diphosphate (ADP)/adenosine triphosphate (ATP) ratio profile of diabetic cardiomyocytes. However, when spatially averaged, myofibrillar ADP/ATP ratios of a cardiomyocyte do not change with diabetes. Instead, average concentration of inorganic phosphate rises by 40% owing to lower mitochondrial area fraction and dysfunction in OXPHOS. These simulations indicate that a disorganized cellular ultrastructure negatively impacts metabolite transport in diabetic cardiomyopathy. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.

Keywords:  cardiomyocyte; computational physiology; diabetes; electron microscopy; heart failure; mitochondria

DOI:  https://doi.org/10.1098/rstb.2021.0323
Proc Natl Acad Sci U S A. 2022 Oct 11. 119(41): e2203628119

Succinyl-CoA-based energy metabolism dysfunction in chronic heart failure.

Shingo Takada, Satoshi Maekawa, Takaaki Furihata, Naoya Kakutani, Daiki Setoyama, Koji Ueda, Hideo Nambu, Hikaru Hagiwara, Haruka Handa, Yoshizuki Fumoto, Soichiro Hata, Tomoka Masunaga, Arata Fukushima, Takashi Yokota, Dongchon Kang, Shintaro Kinugawa, Hisataka Sabe.

  Heart failure (HF) is a leading cause of death and repeated hospitalizations and often involves cardiac mitochondrial dysfunction. However, the underlying mechanisms largely remain elusive. Here, using a mouse model in which myocardial infarction (MI) was induced by coronary artery ligation, we show the metabolic basis of mitochondrial dysfunction in chronic HF. Four weeks after ligation, MI mice showed a significant decrease in myocardial succinyl-CoA levels, and this decrease impaired the mitochondrial oxidative phosphorylation (OXPHOS) capacity. Heme synthesis and ketolysis, and protein levels of several enzymes consuming succinyl-CoA in these events, were increased in MI mice, while enzymes synthesizing succinyl-CoA from α-ketoglutarate and glutamate were also increased. Furthermore, the ADP-specific subunit of succinyl-CoA synthase was reduced, while its GDP-specific subunit was almost unchanged. Administration of 5-aminolevulinic acid, an intermediate in the pathway from succinyl-CoA to heme synthesis, appreciably restored succinyl-CoA levels and OXPHOS capacity and prevented HF progression in MI mice. Previous reports also suggested the presence of succinyl-CoA metabolism abnormalities in cardiac muscles of HF patients. Our results identified that changes in succinyl-CoA usage in different metabolisms of the mitochondrial energy production system is characteristic to chronic HF, and although similar alterations are known to occur in healthy conditions, such as during strenuous exercise, they may often occur irreversibly in chronic HF leading to a decrease in succinyl-CoA. Consequently, nutritional interventions compensating the succinyl-CoA consumption are expected to be promising strategies to treat HF.

Keywords:  5-aminolevulinic acid; heart failure; mitochondria; oxidative phosphorylation; succinyl-CoA

DOI:  https://doi.org/10.1073/pnas.2203628119
J Nutr Biochem. 2022 Sep 29. pii: S0955-2863(22)00229-7. [Epub ahead of print] 109161

Ketogenic diet modulates cardiac metabolic dysregulation in streptozocin-induced diabetic rats.

Nguyen Ngoc Trang, Ting-Wei Lee, Yu-Hsun Kao, Tze-Fan Chao, Ting-I Lee, Yi-Jen Chen.

  The ketogenic diet (KD) might improve cardiac function in diabetic cardiomyopathy, but the mechanisms remain unclear. This study investigated the effects of KD on myocardial fatty acid (FA), glucose, and ketone metabolism in diabetic cardiomyopathy. Echocardiograms, biochemistry, and micro-positron emission tomography (micro-PET) were performed to evaluate cardiac function and glucose uptake in control rats and streptozotocin-induced DM rats with normal diet (ND) or KD for 6 weeks. Histopathology, ATP measurement, and Western blot were performed in the ventricular myocytes to analyze fibrosis, FA, ketone body, and glucose utilization. The ND-fed DM rats exhibited impaired left ventricular systolic function and increased chamber dilatation, whereas control and KD-fed DM rats did not. The KD reduced myocardial fibrosis and apoptosis in the DM rats. Myocardial glucose uptake in the micro-PET was similar between ND-fed DM rats and KD-fed DM rats and was substantially lower than the control rats. Compared with the control rats, ND-fed DM rats had increased phosphorylation of acetyl CoA carboxylase and higher expressions of CD-36, carnitine palmitoyltransferase-1β, tumor necrosis factor-α, interleukin (IL)-1β, IL6, PERK, and e-IF2α as well as more myocardial fibrosis and apoptosis (assessed by Bcl-2, BAX, and caspase-3 expression); these increases were attenuated in the KD-fed DM rats. Moreover, ND-fed DM rats had significantly lower myocardial ATP, BHB, and OXCT1 levels than the control and KD-fed DM rats. The KD may improve the condition of diabetic cardiomyopathy by suppressing FA metabolism, increasing ketone utilization, and decreasing endoplasmic reticulum stress and inflammation.

Keywords:  diabetes mellitus; diabetic cardiomyopathy; fatty acid metabolism; inflammation; ketogenic diet

DOI:  https://doi.org/10.1016/j.jnutbio.2022.109161
Comput Math Methods Med. 2022 ;2022 6260202

Dapagliflozin Inhibits Ventricular Remodeling in Heart Failure Rats by Activating Autophagy through AMPK/mTOR Pathway.

Honghong Ma, Yanmei Ma.

Objective: Heart failure (HF) is the end stage of heart disease caused by various factors which mainly involves ventricular remodeling (VR). In HF patients with reduced ejection fraction, dapagliflozin (DAPA) reduced the risk of worsening HF or cardiovascular death. Thus, we attempted to clarify the specific role of DAPA underlying HF progression.
Methods: The HF rat model was established to mimic characteristics of HF in vivo. HE staining assessed histopathological changes in left ventricular myocardial tissue of rats in each group. ELISA measured plasma ANP and BNP levels of rats in each group. M-mode echocardiography detected cardiac function of rats in each group. TUNEL staining detected apoptosis of infarct margin cells in myocardial tissue of rats in each group. Western blot detected levels of apoptosis-related proteins, autophagy-related proteins, and AMPK/mTOR-related proteins in myocardial tissue of rats in each group. Immunohistochemical staining detected caspase-3 or LC3B level in myocardial tissue of rats in each group. The HF cellular model was established to mimic characteristics of HF in vitro. Flow cytometry detected H9C2 cell apoptosis under different conditions. Western blot detected levels of apoptosis-related proteins, autophagy-related proteins, and AMPK/mTOR-related proteins in H9C2 cells under different conditions. Immunofluorescence detected caspase-3 or LC3B level in H9C2 cells under different conditions.
Results: DAPA attenuated left VR and improved cardiac function in HF rats. DAPA attenuated cardiomyocyte apoptosis in HF rats. DAPA facilitated cardiomyocyte autophagy in HF rats via the AMPK/mTOR pathway. DAPA repressed hypoxia-induced H9C2 cell apoptosis by facilitating autophagy. DAPA repressed hypoxia-induced H9C2 cell apoptosis via the AMPK/mTOR pathway.
Conclusion: DAPA suppresses ventricular remodeling in HF through activating autophagy via AMPK/mTOR pathway, which provides a potential novel insight for seeking therapeutic plans of HF.

DOI: https://doi.org/10.1155/2022/6260202