bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2022‒05‒01
six papers selected by
Kyle McCommis
Saint Louis University
  1. Increased fatty acid metabolism attenuates cardiac resistance to β-adrenoceptor activation via mitochondrial reactive oxygen species: A potential mechanism of hypoglycemia-induced myocardial injury in diabetes.
  2. Salidroside Ameliorates Cardiomyocyte Hypertrophy by Upregulating Peroxisome Proliferator-Activated Receptor-α.
  3. RIP3 Contributes to Cardiac Hypertrophy by Influencing MLKL-Mediated Calcium Influx.
  4. OXPHOS deficiencies affect peroxisome proliferation by downregulating genes controlled by the SNF1 signaling pathway.
  5. Comparison of Serum Ketone Levels and Cardiometabolic Efficacy of Dapagliflozin versus Sitagliptin among Insulin-Treated Chinese Patients with Type 2 Diabetes Mellitus.
  6. α-Tubulin acetylation on Lysine 40 controls cardiac glucose uptake.
  1. Redox Biol. 2022 Apr 21. pii: S2213-2317(22)00092-1. [Epub ahead of print]52 102320
    Increased fatty acid metabolism attenuates cardiac resistance to β-adrenoceptor activation via mitochondrial reactive oxygen species: A potential mechanism of hypoglycemia-induced myocardial injury in diabetes.
    Lishan Huang, Zhou Chen, Ruiyu Chen, Lu Lin, Lingjia Ren, Meilian Zhang, Libin Liu.
      The mechanism of severe hypoglycemia (SH)-induced cardiovascular disease in diabetes remains unknown. Our previous study found that SH inhibits cardiac function and lipid metabolism in diabetic mice. Conversely, in nondiabetic mice, SH does not induce cardiac dysfunction but promotes cardiac lipid metabolism. This study aims to clarify the effect of increased fatty acid metabolism on the resistance of cardiomyocytes to β-adrenoceptor activation during hypoglycemia in diabetes. Results revealed that cardiomyocytes with enhanced lipid metabolism were more vulnerable to damage due to β-adrenoceptor activation, which presented as decreased cell viability, disorder of mitochondrial structure, dissipation of mitochondrial membrane potential, dysfunction of mitochondrial oxidative phosphorylation, nonapoptotic damage, and accumulation of ROS and calcium from mitochondria to cytoplasm, all of which were partially reversed by mitochondrial antioxidant Mito-TEMPO. The SH-induced cardiac dysfunction, and reduction of myocardial energy metabolism in diabetic mice were rescued by Mito-TEMPO. Our findings indicate that high fatty acid metabolism crippled cardiac resistance to β-adrenoceptor hyperactivation, with mitochondrial ROS playing a pivotal role in this process. Reducing mitochondrial ROS in diabetes could disrupt this synergistic effect and prevent poor cardiac outcomes caused by SH.
    Keywords:  Diabetes; Hypoglycemia; Lipid metabolism; Mitochondrial reactive oxygen species; β-adrenoceptor
    DOI:  https://doi.org/10.1016/j.redox.2022.102320
  2. Front Pharmacol. 2022 ;13 865434
    Salidroside Ameliorates Cardiomyocyte Hypertrophy by Upregulating Peroxisome Proliferator-Activated Receptor-α.
    Hui Gao, Kunming Tian, Yichong Meng, Xueping Liu, Yingfu Peng.
      Cardiac hypertrophy is an adaptive change in response to pressure overload, however the hypertrophy may evolve toward heart failure if cannot be corrected as soon as possible. The dysfunction of peroxisome proliferator-activated receptor-α (PPARα) plays a key role in cardiac hypertrophy. In the present study, salidroside inhibited the mRNA expressions of hypertrophic markers including atrial natriuretic factor and brain natriuretic peptide in a dosage-dependent manner. Furthermore, the protein expression and transcriptional activity of PPARα were increased by salidroside in H9C2 cells treated with angiotensin II, as well as the target genes of PPARα, while the situations were nearly reversed when PPARα was knocked down. Next, salidroside could elevate the expression of ATGL, a key upstream regulator of PPARα; the effects of salidroside including increasing PPARα function and inhibiting cardiomyocyte hypertrophy were impaired by ATGL knockdown. Our present studies suggested that salidroside elevated PPARα function to alleviate cardiomyocyte hypertrophy, which was involved in the increase of ATGL expression.
    Keywords:  ATGL; PPARα; cardiac hypertrophy; energy metabolism; salidroside
    DOI:  https://doi.org/10.3389/fphar.2022.865434
  3. Oxid Med Cell Longev. 2022 ;2022 5490553
    RIP3 Contributes to Cardiac Hypertrophy by Influencing MLKL-Mediated Calcium Influx.
    Honghong Xue, Hongtao Shi, Fan Zhang, Hao Li, Chao Li, Qinghua Han.
      Receptor-interacting protein 3(RIP3), a RIP family member, has been reported as a critical regulator of necroptosis and involves in the pathogenesis of various heart diseases. However, its role in the development of myocardial hypertrophy after pressure overload is unclear. We aimed to investigate the roles of RIP3 in pathological cardiac hypertrophy. A rat model of myocardial hypertrophy induced by the aortic banding method was used in this study. Neonatal rat cardiomyocytes (NRCMs) were stimulated with angiotensin II (Ang-II) or phenylephrine (PE) to induce neurohumoral stress. Our results showed that RIP3 level was significantly elevated in the hypertrophic myocardium tissues from patients, rats subjected to AB surgery, and NRCMs treated with Ang-II or PE. After downregulation of RIP3 expression in NRCMs, the phenotypes of myocardial hypertrophy were obviously alleviated. In mechanism, we demonstrated that RIP3 interacts with mixed lineage kinase domain-like protein (MLKL) and promotes its cell membrane localization to increase the influx of calcium within cells, thereby mediating the development of myocardial hypertrophy. More interestingly, we found the blockage of calcium influx by 2-aminoethoxydiphenyl borate, and lanthanum chloride efficiently reverses RIP3-induced cardiac remodeling in NRCMs. Taken together, our findings indicate a key role of the RIP3-MLKL signaling pathway in myocardial hypertrophy, which may be a novel promising treatment strategy for myocardial hypertrophy.
    DOI:  https://doi.org/10.1155/2022/5490553
  4. Elife. 2022 Apr 25. pii: e75143. [Epub ahead of print]11
    OXPHOS deficiencies affect peroxisome proliferation by downregulating genes controlled by the SNF1 signaling pathway.
    Jean-Claude Farre, Krypton Carolino, Lou Devanneaux, Suresh Subramani.
      How environmental cues influence peroxisome proliferation, particularly through organelles, remains largely unknown. Yeast peroxisomes metabolize fatty acids (FA), and methylotrophic yeasts also metabolize methanol. NADH and acetyl-CoA, produced by these pathways enter mitochondria for ATP production and for anabolic reactions. During the metabolism of FA and/or methanol, the mitochondrial oxidative phosphorylation (OXPHOS) pathway accepts NADH for ATP production and maintains cellular redox balance. Remarkably, peroxisome proliferation in Pichia pastoris was abolished in NADH shuttling- and OXPHOS mutants affecting complex I or III, or by the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), indicating ATP depletion causes the phenotype. We show that mitochondrial OXPHOS deficiency inhibits expression of several peroxisomal proteins implicated in FA and methanol metabolism, as well as in peroxisome division and proliferation. These genes are regulated by the Snf1 complex (SNF1), a pathway generally activated by a high AMP/ATP ratio. In OXPHOS mutants, Snf1 is activated by phosphorylation, but Gal83, its interacting subunit, fails to translocate to the nucleus. Phenotypic defects in peroxisome proliferation observed in the OXPHOS mutants, and phenocopied by the Dgal83 mutant, were rescued by deletion of three transcriptional repressor genes (MIG1, MIG2 and NRG1) controlled by SNF1 signaling. Our results are interpreted in terms of a mechanism by which peroxisomal and mitochondrial proteins and/or metabolites influence redox and energy metabolism, while also influencing peroxisome biogenesis and proliferation, thereby exemplifying interorganellar communication and interplay involving peroxisomes, mitochondria, cytosol and the nucleus. We discuss the physiological relevance of this work in the context of human OXPHOS deficiencies.
    Keywords:  cell biology
    DOI:  https://doi.org/10.7554/eLife.75143
  5. Diabetes Metab J. 2022 Apr 28.
    Comparison of Serum Ketone Levels and Cardiometabolic Efficacy of Dapagliflozin versus Sitagliptin among Insulin-Treated Chinese Patients with Type 2 Diabetes Mellitus.
    Chi-Ho Lee, Mei-Zhen Wu, David Tak-Wai Lui, Darren Shing-Hei Chan, Carol Ho-Yi Fong, Sammy Wing-Ming Shiu, Ying Wong, Alan Chun-Hong Lee, Joanne King-Yan Lam, Yu-Cho Woo, Karen Siu-Ling Lam, Kelvin Kai-Hang Yiu, Kathryn Choon-Beng Tan.
      Background: Insulin-treated patients with long duration of type 2 diabetes mellitus (T2DM) are at increased risk of ketoacidosis related to sodium-glucose co-transporter 2 inhibitor (SGLT2i). The extent of circulating ketone elevation in these patients remains unknown. We conducted this study to compare the serum ketone response between dapagliflozin, an SGLT2i, and sitagliptin, a dipeptidyl peptidase-4 inhibitor, among insulin-treated T2DM patients.Methods: This was a randomized, open-label, active comparator-controlled study involving 60 insulin-treated T2DM patients. Participants were randomized 1:1 for 24-week of dapagliflozin 10 mg daily or sitagliptin 100 mg daily. Serum β-hydroxybutyrate (BHB) levels were measured at baseline, 12 and 24 weeks after intervention. Comprehensive cardiometabolic assessments were performed with measurements of high-density lipoprotein cholesterol (HDL-C) cholesterol efflux capacity (CEC), vibration-controlled transient elastography and echocardiography.
    Results: Among these 60 insulin-treated participants (mean age 58.8 years, diabetes duration 18.2 years, glycosylated hemoglobin 8.87%), as compared with sitagliptin, serum BHB levels increased significantly after 24 weeks of dapagliflozin (P=0.045), with a median of 27% increase from baseline. Change in serum BHB levels correlated significantly with change in free fatty acid levels. Despite similar glucose lowering, dapagliflozin led to significant improvements in body weight (P=0.006), waist circumference (P=0.028), HDL-C (P=0.041), CEC (P=0.045), controlled attenuation parameter (P=0.007), and liver stiffness (P=0.022). Average E/e', an echocardiographic index of left ventricular diastolic dysfunction, was also significantly lower at 24 weeks in participants treated with dapagliflozin (P=0.037).
    Conclusion: Among insulin-treated T2DM patients with long diabetes duration, compared to sitagliptin, dapagliflozin modestly increased ketone levels and was associated with cardiometabolic benefits.
    Keywords:  Dapagliflozin; Diabetes mellitus, type 2; Heart disease risk factors; Ketones; Sitagliptin phosphate
    DOI:  https://doi.org/10.4093/dmj.2021.0319
  6. Am J Physiol Heart Circ Physiol. 2022 Apr 29.
    α-Tubulin acetylation on Lysine 40 controls cardiac glucose uptake.
    Edith Renguet, Marine De Loof, Natacha Fourny, Audrey Ginion, Caroline Bouzin, Christian Poüs, Sandrine Horman, Christophe Beauloye, Laurent Bultot, Luc Bertrand.
      Our group previously demonstrated that an excess of nutrients, as observed in diabetes, provokes an increase in cardiac protein acetylation responsible for a reduced insulin-stimulated translocation of the glucose transporter GLUT4 to the plasma membrane. The acetylated proteins involved in this event have yet not been identified. α-Tubulin is a promising candidate as a major cytoskeleton component involved, among other things, in the translocation of GLUT4-containing vesicles from their intracellular pools towards the plasma membrane. Moreover, α-tubulin is known to be acetylated, Lys40 (K40) being its best characterized acetylated residue. The present work sought to evaluate the impact of α-tubulin K40 acetylation on cardiac glucose entry, with a particular interest in GLUT4 translocation. First, we observed that a mouse model of high-fat diet-induced obesity presented an increase in cardiac α-tubulin K40 acetylation level. Next, we showed that treatment of insulin-sensitive primary cultured adult rat cardiomyocytes with tubacin, a specific tubulin acetylation inducer, reduced insulin-stimulated glucose uptake and GLUT4 translocation. Conversely, decreasing α-tubulin K40 acetylation by expressing a non-acetylable dominant form of α-tubulin (mCherry α-tubulin K40A mutant) remarkably intensified insulin-induced glucose transport. Finally, mCherry α-tubulin K40A expression similarly improved glucose transport in insulin-resistant cardiomyocytes or after AMP-activated protein kinase activation. Taken together, our study demonstrates that modulation of α-tubulin K40 acetylation level affects glucose transport in cardiomyocytes, offering new putative therapeutic insights regarding modulation of glucose metabolism in insulin-resistant and diabetic hearts.
    Keywords:  Acetylation; Cardiac metabolism; Glucose uptake; Insulin; Tubulin
    DOI:  https://doi.org/10.1152/ajpheart.00664.2021
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