bims-carmet 2022-01-16 papers

bims-carmet

Biomed News

on Cardiac metabolism

Issue of 2022‒01‒16
seven papers selected by
Mikky Atsér
University of British Columbia

Copper modulates heart mitochondrial H2O2 emission differently during fatty acid and pyruvate oxidation.
Impaired tricarboxylic acid cycle flux and mitochondrial aerobic respiration during isoproterenol induced myocardial ischemia is rescued by bilobalide.
Multi-Omics Approach Profiling Metabolic Remodeling in Early Systolic Dysfunction and in Overt Systolic Heart Failure.
Metabolic Therapy of Heart Failure: Is There a Future for B Vitamins?
Mechanisms of cardiac dysfunction in diabetic cardiomyopathy: molecular abnormalities and phenotypical variants.
Propionate alleviates myocardial ischemia-reperfusion injury aggravated by Angiotensin II dependent on caveolin-1/ACE2 axis through GPR41.
Targeting cardiomyocyte proliferation as a key approach of promoting heart repair after injury.

Comp Biochem Physiol C Toxicol Pharmacol. 2022 Jan 10. pii: S1532-0456(22)00002-3. [Epub ahead of print] 109267

Copper modulates heart mitochondrial H2O2 emission differently during fatty acid and pyruvate oxidation.

Michael O Isei, Don Stevens, Collins Kamunde.

  Although the preferred cardiac metabolic fuels are fatty acids, glucose metabolism also plays an important role. However, irrespective of substrate type, energy generation results in mitochondrial reactive oxygen species (ROS) formation. To determine if the preference of fat over carbohydrates predisposes cardiomyocytes to oxidant production, we measured total and site-specific H2O2 emission in heart mitochondria oxidizing palmitoylcarnitine or pyruvate during copper (Cu) exposure. H2O2 emission was higher during oxidation of palmitoylcarnitine compared with pyruvate. Moreover, the bulk of the H2O2 emitted during palmitoylcarnitine oxidation originated from the outer ubiquinone binding site of complex III (site IIIQo) and the flavin site of electron transfer flavoprotein (site EF). We found no evidence of ROS production from complex I ubiquinone-binding site (site IQ) by reverse electron transport during oxidation of palmitoylcarnitine. Pyruvate oxidation also drove H2O2 emission primarily from sites IIIQo; however, the flavin sites of pyruvate dehydrogenase (site PF) and complex II (site IIF) contributed substantially. The effect of Cu depended on substrate and redox site, with effects at sites OF and IIIQo being more pronounced in mitochondria oxidizing pyruvate compared with palmitoylcarnitine. Cu imposed a concentration-saturable effect at site PF but concentration-dependently stimulated H2O2 emission at site EF. The substrate-dependent differences in H2O2 emission and effects of Cu suggest that fuel type and points of entry of electrons into the mitochondrial electron transport system determine the mitochondrial ROS production rate. Importantly, knowledge of sites of mitochondrial ROS production is crucial to the understanding of cardiac dysfunction associated with impaired substrate metabolism.

Keywords:  Copper; Fish; Heart mitochondria; Metabolic substrate preference; Total and site-specific ROS production

DOI:  https://doi.org/10.1016/j.cbpc.2022.109267
J Pharm Anal. 2021 Dec;11(6): 764-775

Impaired tricarboxylic acid cycle flux and mitochondrial aerobic respiration during isoproterenol induced myocardial ischemia is rescued by bilobalide.

Zhe Wang, Fan Zhang, Wei Liu, Ning Sheng, Hua Sun, Jinlan Zhang.

  There is an urgent need to elucidate the pathogenesis of myocardial ischemia (MI) and potential drug treatments. Here, the anti-MI mechanism and material basis of Ginkgo biloba L. extract (GBE) were studied from the perspective of energy metabolism flux regulation. Metabolic flux analysis (MFA) was performed to investigate energy metabolism flux disorder and the regulatory nodes of GBE components in isoproterenol (ISO)-induced ischemia-like cardiomyocytes. It showed that [U-13C] glucose derived m+2 isotopologues from the upstream tricarboxylic acid (TCA) cycle metabolites were markedly accumulated in ISO-injured cardiomyocytes, but the opposite was seen for the downstream metabolites, while their total cellular concentrations were increased. This indicates a blockage of carbon flow from glycolysis and enhanced anaplerosis from other carbon sources. A Seahorse test was used to screen for GBE components with regulatory effects on mitochondrial aerobic respiratory dysfunction. It showed that bilobalide protected against impaired mitochondrial aerobic respiration. MFA also showed that bilobalide significantly modulated the TCA cycle flux, reduced abnormal metabolite accumulation, and balanced the demand of different carbon sources. Western blotting and PCR analysis showed that bilobalide decreased the enhanced expression of key metabolic enzymes in injured cells. Bilobalide's efficacy was verified by in vivo experiments in rats. This is the first report to show that bilobalide, the active ingredient of GBE, protects against MI by rescuing impaired TCA cycle flux. This provides a new mechanism and potential drug treatment for MI. It also shows the potential of MFA/Seahorse combination as a powerful strategy for pharmacological research on herbal medicine.

Keywords:  Bilobalide; Isoproterenol-induced myocardial ischemia; Seahorse test; Stable isotopic tracing metabolic flux analysis; Tricarboxylic acid cycle

DOI:  https://doi.org/10.1016/j.jpha.2020.08.008
Int J Mol Sci. 2021 Dec 26. pii: 235. [Epub ahead of print]23(1):

Multi-Omics Approach Profiling Metabolic Remodeling in Early Systolic Dysfunction and in Overt Systolic Heart Failure.

Antoine H Chaanine, LeeAnn Higgins, Todd Markowski, Jarrod Harman, Maureen Kachman, Charles Burant, L Gabriel Navar, David Busija, Patrice Delafontaine.

  Metabolic remodeling plays an important role in the pathophysiology of heart failure (HF). We sought to characterize metabolic remodeling and implicated signaling pathways in two rat models of early systolic dysfunction (MOD), and overt systolic HF (SHF). Tandem mass tag-labeled shotgun proteomics, phospho-(p)-proteomics, and non-targeted metabolomics analyses were performed in left ventricular myocardium tissue from Sham, MOD, and SHF using liquid chromatography-mass spectrometry, n = 3 biological samples per group. Mitochondrial proteins were predominantly down-regulated in MOD (125) and SHF (328) vs. Sham. Of these, 82% (103/125) and 66% (218/328) were involved in metabolism and respiration. Oxidative phosphorylation, mitochondrial fatty acid β-oxidation, Krebs cycle, branched-chain amino acids, and amino acid (glutamine and tryptophan) degradation were highly enriched metabolic pathways that decreased in SHF > MOD. Glycogen and glucose degradation increased predominantly in MOD, whereas glycolysis and pyruvate metabolism decreased predominantly in SHF. PKA signaling at the endoplasmic reticulum-mt interface was attenuated in MOD, whereas overall PKA and AMPK cellular signaling were attenuated in SHF vs. Sham. In conclusion, metabolic remodeling plays an important role in myocardial remodeling. PKA and AMPK signaling crosstalk governs metabolic remodeling in progression to SHF.

Keywords:  AMPK; PKA; calcium cycling; heart failure; metabolic remodeling; mitochondria

DOI:  https://doi.org/10.3390/ijms23010235
Int J Mol Sci. 2021 Dec 21. pii: 30. [Epub ahead of print]23(1):

Metabolic Therapy of Heart Failure: Is There a Future for B Vitamins?

Jérôme Piquereau, Solène E Boitard, Renée Ventura-Clapier, Mathias Mericskay.

  Heart failure (HF) is a plague of the aging population in industrialized countries that continues to cause many deaths despite intensive research into more effective treatments. Although the therapeutic arsenal to face heart failure has been expanding, the relatively short life expectancy of HF patients is pushing towards novel therapeutic strategies. Heart failure is associated with drastic metabolic disorders, including severe myocardial mitochondrial dysfunction and systemic nutrient deprivation secondary to severe cardiac dysfunction. To date, no effective therapy has been developed to restore the cardiac energy metabolism of the failing myocardium, mainly due to the metabolic complexity and intertwining of the involved processes. Recent years have witnessed a growing scientific interest in natural molecules that play a pivotal role in energy metabolism with promising therapeutic effects against heart failure. Among these molecules, B vitamins are a class of water soluble vitamins that are directly involved in energy metabolism and are of particular interest since they are intimately linked to energy metabolism and HF patients are often B vitamin deficient. This review aims at assessing the value of B vitamin supplementation in the treatment of heart failure.

Keywords:  B vitamins; cobalamin; energy metabolism; folate; heart failure; metabolic therapy; mitochondria; nicotinamide; pyridoxine; riboflavin; thiamin

DOI:  https://doi.org/10.3390/ijms23010030
Heart Fail Rev. 2022 Jan 10.

Mechanisms of cardiac dysfunction in diabetic cardiomyopathy: molecular abnormalities and phenotypical variants.

Francesca Romana Prandi, Isabella Evangelista, Domenico Sergi, Alberto Palazzuoli, Francesco Romeo.

  Diabetic cardiomyopathy (DCM) is a diabetes mellitus-induced pathophysiological condition characterized by cardiac structural, functional, and metabolic changes that can result in heart failure (HF), in the absence of coronary artery disease, hypertension, and valvular heart disease. Metabolic alterations such as hyperglycemia, insulin resistance, hyperinsulinemia, and increased metabolism of free fatty acids result in oxidative stress, inflammation, advanced glycation end products formation, abnormalities in calcium homeostasis, and apoptosis that are responsible for structural remodeling. Cardiac stiffness, hypertrophy, and fibrosis eventually lead to dysfunction and HF with preserved ejection fraction and/or HF with reduced ejection fraction. In this review, we analyzed in detail the cellular and molecular mechanisms and the metabolic pathways involved in the pathophysiology of DCM. Different phenotypes are observed in DCM, and it is not clear yet if the restrictive and the dilated phenotypes are distinct or represent an evolution of the same disease. Phenotypic differences can be observed between T1DM and T2DM DCM, possibly explained by the different myocardial insulin action. Further studies are needed in order to better understand the underlying mechanisms of DCM and to identify appropriate therapeutic targets and novel strategies to prevent and reverse the progression toward heart failure in diabetic patients.

Keywords:  Diabetes mellitus; Diabetic cardiomyopathy; Heart failure; Restrictive phenotype

DOI:  https://doi.org/10.1007/s10741-021-10200-y
Int J Biol Sci. 2022 ;18(2): 858-872

Propionate alleviates myocardial ischemia-reperfusion injury aggravated by Angiotensin II dependent on caveolin-1/ACE2 axis through GPR41.

Fan Deng, Liang-Qing Zhang, Han Wu, Yu Chen, Wen-Qian Yu, Rong-Hui Han, Yuan Han, Xiao-Qi Zhang, Qi-Shun Sun, Ze-Bin Lin, Yu Wang, Yong-Pan Liu, Jing-Yi Chen, Ke-Xuan Liu, Jing-Juan Hu.

  Myocardial ischemia/reperfusion (I/R) injury is still a lack of effective therapeutic drugs, and its molecular mechanism is urgently needed. Studies have shown that the intestinal flora plays an important regulatory role in cardiovascular injury, but the specific mechanism has not been fully elucidated. In this study, we found that an increase in Ang II in plasma was accompanied by an increase in the levels of myocardial injury during myocardial reperfusion in patients with cardiopulmonary bypass. Furthermore, Ang II treatment enhanced mice myocardial I/R injury, which was reversed by caveolin-1 (CAV-1)-shRNA or strengthened by angiotensin-converting enzyme 2 (ACE2)-shRNA. The results showed that CAV-1 and ACE2 have protein interactions and inhibit each other's expression. In addition, propionate, a bacterial metabolite, inhibited the elevation of Ang II and myocardial injury, while GPR41-shRNA abolished the protective effects of propionate on myocardial I/R injury. Clinically, the propionate content in the patient's preoperative stool was related to Ang II levels and myocardial I/R injury levels during myocardial reperfusion. Taken together, propionate alleviates myocardial I/R injury aggravated by Ang II dependent on CAV-1/ACE2 axis through GPR41, which provides a new direction that diet to regulate the intestinal flora for treatment of myocardial I/R injury.

Keywords:  Angiotensin II; Angiotensin-converting enzyme 2; Caveolin-1; G-protein coupled receptor 41.; Myocardial ischemia reperfusion; Propionate

DOI:  https://doi.org/10.7150/ijbs.67724
Mol Biomed. 2021 Nov 05. 2(1): 34

Targeting cardiomyocyte proliferation as a key approach of promoting heart repair after injury.

Shuainan Li, Wenya Ma, Benzhi Cai.

  Cardiovascular diseases such as myocardial infarction (MI) is a major contributor to human mortality and morbidity. The mammalian adult heart almost loses its plasticity to appreciably regenerate new cardiomyocytes after injuries, such as MI and heart failure. The neonatal heart exhibits robust proliferative capacity when exposed to varying forms of myocardial damage. The ability of the neonatal heart to repair the injury and prevent pathological left ventricular remodeling leads to preserved or improved cardiac function. Therefore, promoting cardiomyocyte proliferation after injuries to reinitiate the process of cardiomyocyte regeneration, and suppress heart failure and other serious cardiovascular problems have become the primary goal of many researchers. Here, we review recent studies in this field and summarize the factors that act upon the proliferation of cardiomyocytes and cardiac repair after injury and discuss the new possibilities for potential clinical treatment strategies for cardiovascular diseases.

Keywords:  Cardiac repair; Cardiomyocyte proliferation; Cardiovascular disease; Heart regeneration; MicroRNAs; Myocardial infarction

DOI:  https://doi.org/10.1186/s43556-021-00047-y