bims-hafaim 2022-06-05 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022‒06‒05
six papers selected by
Kyle McCommis
Saint Louis University

Direct Cardiac Actions of Sodium-Glucose Cotransporter 2 Inhibition Improve Mitochondrial Function and Attenuate Oxidative Stress in Pressure Overload-Induced Heart Failure.
MCC950, a Selective NLRP3 Inhibitor, Attenuates Adverse Cardiac Remodeling Following Heart Failure Through Improving the Cardiometabolic Dysfunction in Obese Mice.
Pyruvate Kinase M2 Protects Heart from Pressure Overload-Induced Heart Failure by Phosphorylating RAC1.
Effects of Short Term Adiponectin Receptor Agonism on Cardiac Function and Energetics in Diabetic db/db Mice.
Urolithin A ameliorates obesity-induced metabolic cardiomyopathy in mice via mitophagy activation.
Plasma metabolites associated with functional and clinical outcomes in heart failure with reduced ejection fraction with and without type 2 diabetes.

Front Cardiovasc Med. 2022 ;9 859253

Direct Cardiac Actions of Sodium-Glucose Cotransporter 2 Inhibition Improve Mitochondrial Function and Attenuate Oxidative Stress in Pressure Overload-Induced Heart Failure.

Xuan Li, Elizabeth R Flynn, Jussara M do Carmo, Zhen Wang, Alexandre A da Silva, Alan J Mouton, Ana C M Omoto, Michael E Hall, John E Hall.

  Clinical trials showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors, a class of drugs developed for treating diabetes mellitus, improve prognosis of patients with heart failure (HF). However, the mechanisms for cardioprotection by SGLT2 inhibitors are still unclear. Mitochondrial dysfunction and oxidative stress play important roles in progression of HF. This study tested the hypothesis that empagliflozin (EMPA), a highly selective SGLT2 inhibitor, improves mitochondrial function and reduces reactive oxygen species (ROS) while enhancing cardiac performance through direct effects on the heart in a non-diabetic mouse model of HF induced by transverse aortic constriction (TAC). EMPA or vehicle was administered orally for 4 weeks starting 2 weeks post-TAC. EMPA treatment did not alter blood glucose or body weight but significantly attenuated TAC-induced cardiac dysfunction and ventricular remodeling. Impaired mitochondrial oxidative phosphorylation (OXPHOS) in failing hearts was significantly improved by EMPA. EMPA treatment also enhanced mitochondrial biogenesis and restored normal mitochondria morphology. Although TAC increased mitochondrial ROS and decreased endogenous antioxidants, EMPA markedly inhibited cardiac ROS production and upregulated expression of endogenous antioxidants. In addition, EMPA enhanced autophagy and decreased cardiac apoptosis in TAC-induced HF. Importantly, mitochondrial respiration significantly increased in ex vivo cardiac fibers after direct treatment with EMPA. Our results indicate that EMPA has direct effects on the heart, independently of reductions in blood glucose, to enhance mitochondrial function by upregulating mitochondrial biogenesis, enhancing OXPHOS, reducing ROS production, attenuating apoptosis, and increasing autophagy to improve overall cardiac function in a non-diabetic model of pressure overload-induced HF.

Keywords:  apoptosis; autophagy; empagliflozin; heart failure; mitochondrial biogenesis; reactive oxidative species; sodium-glucose cotransporter 2

DOI:  https://doi.org/10.3389/fcvm.2022.859253
Front Cardiovasc Med. 2022 ;9 727474

MCC950, a Selective NLRP3 Inhibitor, Attenuates Adverse Cardiac Remodeling Following Heart Failure Through Improving the Cardiometabolic Dysfunction in Obese Mice.

Menglong Wang, Mengmeng Zhao, Junping Yu, Yao Xu, Jishou Zhang, Jianfang Liu, Zihui Zheng, Jing Ye, Zhen Wang, Di Ye, Yongqi Feng, Shuwan Xu, Wei Pan, Cheng Wei, Jun Wan.

  Obesity is often accompanied by hypertension. Although a large number of studies have confirmed that NLRP3 inhibitors can improve cardiac remodeling in mice with a normal diet, it is still unclear whether NLRP3 inhibitors can improve heart failure (HF) induced by pressure overload in obese mice. The purpose of this study was to explore the role of MCC950, a selective NLRP3 inhibitor, on HF in obese mice and its metabolic mechanism. Obese mice induced with a 10-week high-fat diet (HFD) were used in this study. After 4 weeks of HFD, transverse aortic constriction (TAC) surgery was performed to induce a HF model. MCC950 (10 mg/kg, once/day) was injected intraperitoneally from 2 weeks after TAC and continued for 4 weeks. After echocardiography examination, we harvested left ventricle tissues and performed molecular experiments. The results suggest that in obese mice, MCC950 can significantly improve cardiac hypertrophy and fibrosis caused by pressure overload. MCC950 ameliorated cardiac inflammation after TAC surgery and promoted M2 macrophage infiltration in the cardiac tissue. MCC950 not only restored fatty acid uptake and utilization by regulating the expression of CD36 and CPT1β but also reduced glucose uptake and oxidation via regulating the expression of GLUT4 and p-PDH. In addition, MCC950 affected the phosphorylation of AKT and AMPK in obese mice with HF. In summary, MCC950 can alleviate HF induced by pressure overload in obese mice via improving cardiac metabolism, providing a basis for the clinical application of NLRP3 inhibitors in obese patients with HF.

Keywords:  MCC950; cardiac hypertrophy; heart failure; inflammasome; metabolic remodeling; pressure overload

DOI:  https://doi.org/10.3389/fcvm.2022.727474
J Am Heart Assoc. 2022 Jun 03. e024854

Pyruvate Kinase M2 Protects Heart from Pressure Overload-Induced Heart Failure by Phosphorylating RAC1.

Le Ni, Bowen Lin, Lingjie Hu, Ruoyu Zhang, Fengmei Fu, Meiting Shen, Jian Yang, Dan Shi.

  Background Heart failure, caused by sustained pressure overload, remains a major public health problem. PKM (pyruvate kinase M) acts as a rate-limiting enzyme of glycolysis. PKM2 (pyruvate kinase M2), an alternative splicing product of PKM, plays complex roles in various biological processes and diseases. However, the role of PKM2 in the development of heart failure remains unknown. Methods and Results Cardiomyocyte-specific Pkm2 knockout mice were generated by crossing the floxed Pkm2 mice with α-MHC (myosin heavy chain)-Cre transgenic mice, and cardiac specific Pkm2 overexpression mice were established by injecting adeno-associated virus serotype 9 system. The results showed that cardiomyocyte-specific Pkm2 deletion resulted in significant deterioration of cardiac functions under pressure overload, whereas Pkm2 overexpression mitigated transverse aortic constriction-induced cardiac hypertrophy and improved heart functions. Mechanistically, we demonstrated that PKM2 acted as a protein kinase rather than a pyruvate kinase, which inhibited the activation of RAC1 (rho family, small GTP binding protein)-MAPK (mitogen-activated protein kinase) signaling pathway by phosphorylating RAC1 in the progress of heart failure. In addition, blockade of RAC1 through NSC23766, a specific RAC1 inhibitor, attenuated pathological cardiac remodeling in Pkm2 deficiency mice subjected to transverse aortic constriction. Conclusions This study revealed that PKM2 attenuated overload-induced pathological cardiac hypertrophy and heart failure, which provides an attractive target for the prevention and treatment of cardiomyopathies.

Keywords:  heart failure; protein kinase; pyruvate kinase M2; rho family; small GTP binding protein

DOI:  https://doi.org/10.1161/JAHA.121.024854
J Lipid Atheroscler. 2022 May;11(2): 161-177

Effects of Short Term Adiponectin Receptor Agonism on Cardiac Function and Energetics in Diabetic db/db Mice.

Aleksandre Tarkhnishvili, Christoph Koentges, Katharina Pfeil, Johannes Gollmer, Nikole J Byrne, Ivan Vosko, Julia Lueg, Laura Vogelbacher, Stephan Birkle, Sibai Tang, Timothy Bon-Nawul Mwinyella, Michael M Hoffmann, Katja E Odening, Nathaly Anto Michel, Dennis Wolf, Peter Stachon, Ingo Hilgendorf, Markus Wallner, Senka Ljubojevic-Holzer, Dirk von Lewinski, Peter Rainer, Simon Sedej, Harald Sourij, Christoph Bode, Andreas Zirlik, Heiko Bugger.

  Objective: Impaired cardiac efficiency is a hallmark of diabetic cardiomyopathy in models of type 2 diabetes. Adiponectin receptor 1 (AdipoR1) deficiency impairs cardiac efficiency in non-diabetic mice, suggesting that hypoadiponectinemia in type 2 diabetes may contribute to impaired cardiac efficiency due to compromised AdipoR1 signaling. Thus, we investigated whether targeting cardiac adiponectin receptors may improve cardiac function and energetics, and attenuate diabetic cardiomyopathy in type 2 diabetic mice.Methods: A non-selective adiponectin receptor agonist, AdipoRon, and vehicle were injected intraperitoneally into Eight-week-old db/db or C57BLKS/J mice for 10 days. Cardiac morphology and function were evaluated by echocardiography and working heart perfusions.
Results: Based on echocardiography, AdipoRon treatment did not alter ejection fraction, left ventricular diameters or left ventricular wall thickness in db/db mice compared to vehicle-treated mice. In isolated working hearts, an impairment in cardiac output and efficiency in db/db mice was not improved by AdipoRon. Mitochondrial respiratory capacity, respiration in the presence of oligomycin, and 4-hydroxynonenal levels were similar among all groups. However, AdipoRon induced a marked shift in the substrate oxidation pattern in db/db mice towards increased reliance on glucose utilization. In parallel, the diabetes-associated increase in serum triglyceride levels in vehicle-treated db/db mice was blunted by AdipoRon treatment, while an increase in myocardial triglycerides in vehicle-treated db/db mice was not altered by AdipoRon treatment.
Conclusion: AdipoRon treatment shifts myocardial substrate preference towards increased glucose utilization, likely by decreasing fatty acid delivery to the heart, but was not sufficient to improve cardiac output and efficiency in db/db mice.

Keywords:  Adiponectin; Adiponectin receptor; Metabolism; Mitochondria; Myocardial contraction

DOI:  https://doi.org/10.12997/jla.2022.11.2.161
Acta Pharmacol Sin. 2022 Jun 02.

Urolithin A ameliorates obesity-induced metabolic cardiomyopathy in mice via mitophagy activation.

Jian-Rong Huang, Ming-Hua Zhang, Ying-Jie Chen, Yu-Ling Sun, Zhi-Min Gao, Zhuo-Jia Li, Gui-Ping Zhang, Yuan Qin, Xiao-Yan Dai, Xi-Yong Yu, Xiao-Qian Wu.

  Metabolic cardiomyopathy (MC) is characterized by intracellular lipid accumulation and utilizing fatty acids as a foremost energy source, thereby leading to excess oxidative stress and mitochondrial dysfunction. There is no effective therapy available yet. In this study we investigated whether defective mitophagy contributed to MC and whether urolithin A (UA), a naturally occurring microflora-derived metabolite, could protect against MC in experimental obese mice. Mice were fed high fat diet for 20 weeks to establish a diet-induced obese model. We showed that mitochondrial autophagy or mitophagy was significantly downregulated in the heart of experimental obese mice. UA (50 mg·kg-1·d-1, for 4 weeks) markedly activated mitophagy and ameliorated MC in obese mice by gavage. In PA-challenged H9C2 cardiomyocytes, UA (5 μM) significantly increased autophagosomes and decreased autolysosomes. Furthermore, UA administration rescued PINK1/Parkin-dependent mitophagy and relieved mitochondrial defects in the heart of obese mice, which led to improving cardiac diastolic function and ameliorating cardiac remodelling. In PA-challenged primarily isolated cardiomyocytes, both application of mitophagy inhibitor Mdivi-1 (15 μM) and silencing of mitophagy gene Parkin blunted the myocardial protective effect of UA. In summary, our data suggest that restoration of mitophagy with UA ameliorates symptoms of MC, which highlights a therapeutic potential of UA in the treatment of MC.

Keywords:  autophagy; high fat diet; metabolic cardiomyopathy; mitochondrial dysfunction; mitophagy; obesity

DOI:  https://doi.org/10.1038/s41401-022-00919-1
Sci Rep. 2022 Jun 02. 12(1): 9183

Plasma metabolites associated with functional and clinical outcomes in heart failure with reduced ejection fraction with and without type 2 diabetes.

Joseph B Lerman, Stephanie N Giamberardino, Adrian F Hernandez, G Michael Felker, Svati H Shah, Robert W McGarrah.

Heart failure with reduced ejection fraction (HFrEF) is increasingly treated with medications for type 2 diabetes mellitus (T2DM). Whether metabolic derangements in HFrEF and T2DM are associated with differential outcomes remains unclear. Therefore, understanding molecular pathways in HFrEF and T2DM and their effects on clinical endpoints is important. The FIGHT trial randomized 300 individuals with HFrEF and a recent HF hospitalization to liraglutide (a GLP-1 receptor agonist) versus placebo to assess effects on mortality, HF rehospitalization, and 6-month change in NT-ProBNP. Although the trial showed no clinical benefit of liraglutide, the trial population was highly enriched for individuals with T2DM. Sixty metabolites were quantified via mass spectrometry in plasma from 254 FIGHT participants (N = 147 (57.9%) with T2DM). Principal components analysis reduced the high number of correlated metabolites into uncorrelated factors. The association of factor levels with 90-day changes in 6-min walk distance (6MWD) and NT-proBNP, and with time to mortality or HF hospitalization were evaluated. There were no changes in metabolite factors according to treatment assignment. However, in analyses stratified by T2DM status, changes in five plasma metabolite factors correlated with changes in functional outcomes beyond adjustment: factor 2 (branched-chain amino acids [BCAA]) correlated with changes in NT-proBNP (ρ = - 0.291, p = 4 × 10-4) and 6MWD (ρ= 0.265, p = 0.011); factor 1 (medium-chain acylcarnitines; ρ = 0.220, p = 0.008), factor 4 (long-chain dicarboxylacylcarnitines; ρ = 0.191, p = 0.019), factor 5 (long-chain acylcarnitines; ρ = 0.198, p = 0.017), and factor 8 (urea cycle metabolites; ρ = - 0.239, p = 4 × 10-3), correlated with change in NT-proBNP. Factor 4 was associated with time-to-event (HR = 1.513 [95% CI 1.208-1.896], p = 3 × 10-4) with a trend towards stronger prognostic effect in T2DM (T2DM: p = 1 × 10-3, non-T2DM: p = 0.1). We identified metabolites of BCAA, urea cycle and fatty acid metabolism as biomarkers of HFrEF outcomes, with observed differences in HFrEF patients with T2DM. Such biomarkers might enable future diagnostic or therapeutic interventions in individuals with HFrEF and T2DM.Trial Registration: Clinicaltrials.gov. Identifier: NCT01800968. First posted: February 28, 2013.

DOI: https://doi.org/10.1038/s41598-022-12973-0