bims-hafaim 2021-03-21 papers

bims-hafaim

Biomed News

on Heart Failure Metabolism

Issue of 2021‒03‒21
nine papers selected by
Kyle McCommis
Saint Louis University

Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart.
Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction.
Cardiac retinoic acid levels decline in heart failure.
Deletion of Smad3 protects against diabetic myocardiopathy in db/db mice.
Direct Cardiac Actions of the Sodium Glucose Co-Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure-Overload Heart Failure.
Macrophage p47phox Regulates Pressure Overload-Induced Left Ventricular Remodelling by Modulating IL-4/STAT6/PPARγ Signaling.
A Review of the Proposed Mechanistic Actions of Sodium Glucose Cotransporter-2 Inhibitors in the Treatment of Heart Failure.
Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial.
Combination of Linagliptin and Empagliflozin Preserves Cardiac Systolic Function in an Ischemia-Reperfusion Injury Mice With Diabetes Mellitus.

Nat Commun. 2021 03 15. 12(1): 1680

Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart.

Jacquelyn M Walejko, Bridgette A Christopher, Scott B Crown, Guo-Fang Zhang, Adrian Pickar-Oliver, Takeshi Yoneshiro, Matthew W Foster, Stephani Page, Stephan van Vliet, Olga Ilkayeva, Michael J Muehlbauer, Matthew W Carson, Joseph T Brozinick, Craig D Hammond, Ruth E Gimeno, M Arthur Moseley, Shingo Kajimura, Charles A Gersbach, Christopher B Newgard, Phillip J White, Robert W McGarrah.

Branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) are elevated in an array of cardiometabolic diseases. Here we demonstrate that the major metabolic fate of uniformly-13C-labeled α-ketoisovalerate ([U-13C]KIV) in the heart is reamination to valine. Activation of cardiac branched-chain α-ketoacid dehydrogenase (BCKDH) by treatment with the BCKDH kinase inhibitor, BT2, does not impede the strong flux of [U-13C]KIV to valine. Sequestration of BCAA and BCKA away from mitochondrial oxidation is likely due to low levels of expression of the mitochondrial BCAA transporter SLC25A44 in the heart, as its overexpression significantly lowers accumulation of [13C]-labeled valine from [U-13C]KIV. Finally, exposure of perfused hearts to levels of BCKA found in obese rats increases phosphorylation of the translational repressor 4E-BP1 as well as multiple proteins in the MEK-ERK pathway, leading to a doubling of total protein synthesis. These data suggest that elevated BCKA levels found in obesity may contribute to pathologic cardiac hypertrophy via chronic activation of protein synthesis.

DOI: https://doi.org/10.1038/s41467-021-21962-2
Nat Commun. 2021 03 16. 12(1): 1684

Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction.

Gabriele G Schiattarella, Francisco Altamirano, Soo Young Kim, Dan Tong, Anwarul Ferdous, Hande Piristine, Subhajit Dasgupta, Xuliang Wang, Kristin M French, Elisa Villalobos, Stephen B Spurgin, Maayan Waldman, Nan Jiang, Herman I May, Theodore M Hill, Yuxuan Luo, Heesoo Yoo, Vlad G Zaha, Sergio Lavandero, Thomas G Gillette, Joseph A Hill.

Heart failure with preserved ejection fraction (HFpEF) is now the dominant form of heart failure and one for which no efficacious therapies exist. Obesity and lipid mishandling greatly contribute to HFpEF. However, molecular mechanism(s) governing metabolic alterations and perturbations in lipid homeostasis in HFpEF are largely unknown. Here, we report that cardiomyocyte steatosis in HFpEF is coupled with increases in the activity of the transcription factor FoxO1 (Forkhead box protein O1). FoxO1 depletion, as well as over-expression of the Xbp1s (spliced form of the X-box-binding protein 1) arm of the UPR (unfolded protein response) in cardiomyocytes each ameliorates the HFpEF phenotype in mice and reduces myocardial lipid accumulation. Mechanistically, forced expression of Xbp1s in cardiomyocytes triggers ubiquitination and proteasomal degradation of FoxO1 which occurs, in large part, through activation of the E3 ubiquitin ligase STUB1 (STIP1 homology and U-box-containing protein 1) a novel and direct transcriptional target of Xbp1s. Our findings uncover the Xbp1s-FoxO1 axis as a pivotal mechanism in the pathogenesis of cardiometabolic HFpEF and unveil previously unrecognized mechanisms whereby the UPR governs metabolic alterations in cardiomyocytes.

DOI: https://doi.org/10.1038/s41467-021-21931-9
JCI Insight. 2021 Mar 16. pii: 137593. [Epub ahead of print]

Cardiac retinoic acid levels decline in heart failure.

Ni Yang, Lauren Parker, Jianshi Yu, Jace W Jones, Ting Liu, Kyriakos N Papanicolaou, C Conover Talbot, Kenneth B Margulies, Brian O'Rourke, Maureen Kane, D Brian Foster.

  Though low circulating levels of the vitamin A metabolite, all-trans retinoic acid (ATRA), are associated with increased risk of cardiovascular events and all-cause mortality, few studies have addressed whether cardiac retinoid levels are altered in the failing heart. Here, we show that proteomic analyses of human and guinea pig heart failure (HF) are consistent a decline in resident cardiac ATRA. Quantitation of the retinoids in ventricular myocardium by mass spectrometry reveals 32 and 39% ATRA decreases in guinea pig HF and in patients with idiopathic dilated cardiomyopathy (IDCM), respectively, despite ample reserves of cardiac vitamin A. ATRA (2mg/kg/day) is sufficient to mitigate cardiac remodeling and prevent functional decline in guinea pig HF. Though cardiac ATRA declines in both guinea pig HF human IDCM, levels certain retinoid metabolic enzymes diverge. Specifically, high expression of the ATRA-catabolizing enzyme, CYP26A1, in human IDCM could dampen prospects for an ATRA-based therapy. Pertinently, a pan-CYP26 inhibitor, talarozole, abrogates the impact of phenylephrine on ATRA decline and hypertrophy in neonatal rat ventricular myocytes. Taken together, we submit that low cardiac ATRA attenuates the expression of critical ATRA-dependent gene programs in HF and that strategies to normalize ATRA metabolism, like CYP26 inhibition, may have therapeutic potential.

Keywords:  Cardiology; Heart failure

DOI:  https://doi.org/10.1172/jci.insight.137593
J Cell Mol Med. 2021 Mar 17.

Deletion of Smad3 protects against diabetic myocardiopathy in db/db mice.

Li Dong, Jian-Chun Li, Zhong-Jing Hu, Xiao-Ru Huang, Li Wang, Hong-Lian Wang, Ronald C W Ma, Hui-Yao Lan, Si-Jin Yang.

  Diabetic cardiomyopathy (DCM) is a common diabetic complication characterized by diastolic relaxation abnormalities, myocardial fibrosis and chronic heart failure. Although TGF-β/Smad3 signalling has been shown to play a critical role in chronic heart disease, the role and mechanisms of Smad3 in DCM remain unclear. We reported here the potential role of Smad3 in the development of DCM by genetically deleting the Smad3 gene from db/db mice. At the age of 32 weeks, Smad3WT-db/db mice developed moderate to severe DCM as demonstrated by a marked increase in the left ventricular (LV) mass, a significant fall in the LV ejection fraction (EF) and LV fractional shortening (FS), and progressive myocardial fibrosis and inflammation. In contrast, db/db mice lacking Smad3 (Smad3KO-db/db) were protected against the development of DCM with normal cardiac function and undetectable myocardial inflammation and fibrosis. Interestingly, db/db mice with deleting one copy of Smad3 (Smad3 ± db/db) did not show any cardioprotective effects. Mechanistically, we found that deletion of Smad3 from db/db mice largely protected cardiac Smad7 from Smurf2-mediated ubiquitin proteasome degradation, thereby inducing IBα to suppress NF-kB-driven cardiac inflammation. In addition, deletion of Smad3 also altered Smad3-dependent miRNAs by up-regulating cardiac miR-29b while suppressing miR-21 to exhibit the cardioprotective effect on Smad3KO-db/db mice. In conclusion, results from this study reveal that Smad3 is a key mediator in the pathogenesis of DCM. Targeting Smad3 may be a novel therapy for DCM.

Keywords:  Smad3; diabetic myocardiopathy; fibrosis; inflammation; miR-21; miR-29

DOI:  https://doi.org/10.1111/jcmm.16464
J Am Heart Assoc. 2021 Mar 16. 10(6): e018298

Direct Cardiac Actions of the Sodium Glucose Co-Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure-Overload Heart Failure.

Xuan Li, Qingguo Lu, Yunguang Qiu, Jussara M do Carmo, Zhen Wang, Alexandre A da Silva, Alan Mouton, Ana C M Omoto, Michael E Hall, Ji Li, John E Hall.

  Background We determined if the sodium glucose co-transporter 2 inhibitor empagliflozin attenuates pressure overload-induced heart failure in non-diabetic mellitus mice by direct cardiac effects and the mechanisms involved. Methods and Results Male C57BL/6J mice (4-6 months of age) were subjected to sham surgeries or transverse aortic constriction to produce cardiac pressure overload. Two weeks after transverse aortic constriction, empagliflozin (10 mg/kg per day) or vehicle was administered daily for 4 weeks. Empagliflozin increased survival rate and significantly attenuated adverse left ventricle remodeling and cardiac fibrosis after transverse aortic constriction. Empagliflozin also attenuated left ventricular systolic and diastolic dysfunction, evaluated by echocardiography, and increased exercise endurance by 36% in mice with transverse aortic constriction-induced heart failure. Empagliflozin significantly increased glucose and fatty acid oxidation in failing hearts, while reducing glycolysis. These beneficial cardiac effects of empagliflozin occurred despite no significant changes in fasting blood glucose, body weight, or daily urine volume. In vitro experiments in isolated cardiomyocytes indicated that empagliflozin had direct effects to improve cardiomyocyte contractility and calcium transients. Importantly, molecular docking analysis and isolated perfused heart experiments indicated that empagliflozin can bind cardiac glucose transporters to reduce glycolysis, restore activation of adenosine monophosphate-activated protein kinase and inhibit activation of the mammalian target of rapamycin complex 1 pathway. Conclusions Our study demonstrates that empagliflozin may directly bind glucose transporters to reduce glycolysis, rebalance coupling between glycolysis and oxidative phosphorylation, and regulate the adenosine monophosphate-activated protein kinase mammalian target of rapamycin complex 1 pathway to attenuate adverse cardiac remodeling and progression of heart failure induced by pressure-overload in non-diabetic mellitus mice.

Keywords:  cardiac hypertrophy; cardiac metabolism; cardiomyocytes; sodium glucose cotransporter 2; transverse aortic constriction

DOI:  https://doi.org/10.1161/JAHA.120.018298
Free Radic Biol Med. 2021 Mar 15. pii: S0891-5849(21)00159-3. [Epub ahead of print]

Macrophage p47phox Regulates Pressure Overload-Induced Left Ventricular Remodelling by Modulating IL-4/STAT6/PPARγ Signaling.

Sukka Santosh Reddy, Heena Agarwal, Anant Jaiswal, Kumaravelu Jagavelu, Madhu Dikshit, Manoj Kumar Barthwal.

  NADPH oxidase (Nox) mediates ROS production and contributes to cardiac remodeling. However, macrophage p47phox, a Nox subunit regulating cardiac remodeling, is unclear. We aimed to investigate the role of macrophage p47phox in hypertensive cardiac remodeling. Pressure-overload induced by Angiotensin II (AngII) for two weeks in young adult male p47phox deficient (KO) mice showed aggravated cardiac dysfunction and hypertrophy as indicated from echocardiographic and histological studies in comparison with wild-type littermates (WT). Additionally, LV of AngII-infused KO mice showed augmented interstitial fibrosis, collagen deposition and, myofibroblasts compared to AngII-infused WT mice. Moreover, these changes in AngII-infused KO mice correlated well with the gene analysis of hypertrophic and fibrotic markers. Similar results were also found in the transverse aortic constriction model. Further, AngII-infused KO mice showed elevated circulating immunokines and increased LV leukocytes infiltration and CD206+ macrophages compared to AngII-infused WT mice. Likewise, LV of AngII-infused KO mice showed upregulated mRNA expression of anti-inflammatory/pro-fibrotic M2 macrophage markers (Ym1, Arg-1) compared to AngII-infused WT mice. AngII and IL-4 treated bone marrow-derived macrophages (BMDMs) from KO mice showed upregulated M2 macrophage markers and STAT6 phosphorylation (Y641) compared to AngII and IL-4 treated WT BMDMs. These alterations were at least partly mediated by macrophage as bone marrow transplantation from KO mice into WT mice aggravated cardiac remodelling. Mechanistically, AngII-infused KO mice showed hyperactivated IL-4/STAT6/PPARγ signaling and downregulated SOCS3 expression compared to AngII-infused WT mice. Our studies show that macrophage p47phox limits anti-inflammatory signaling and extracellular matrix remodeling in response to pressure-overload.

Keywords:  Angiotensin II; fibrosis; hypertension; hypertrophy; macrophages; p47(phox)

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.03.007
Cardiol Res. 2021 Apr;12(2): 60-66

A Review of the Proposed Mechanistic Actions of Sodium Glucose Cotransporter-2 Inhibitors in the Treatment of Heart Failure.

Brandon Nightingale.

  Diabetes mellitus is a well-known risk factor for heart failure, and the reasons why are well understood. The incidence of diabetes mellitus is continuing to rise, posing a major concern in the medical world. The comorbidities associated with diabetes mellitus create a major hindrance on daily living, and promote the development of a plethora of other diseases. It is known that by controlling modifiable risk factors, such as glycemic control and body mass index, patients achieve more favorable outcomes. But, this is not always realistic and controlling modifiable risk factors should be balanced with a pharmacologic option. A relatively new drug class, which acts as an inhibitor of the sodium glucose cotransporter-2 receptor, has shown favorable outcomes in the treatment of heart failure associated with diabetes. However, the mechanism of action of this new drug class is not fully understood. There are several different proposed mechanisms of action for how sodium glucose cotransporter-2 inhibitors work in regards to the treatment of heart failure. This review will elaborate on those proposed mechanisms of action and offer insight into future implications of this relatively new drug class.

Keywords:  Cardiovascular; Diabetes; Heart failure; Renal; SGLT2

DOI:  https://doi.org/10.14740/cr1221
J Am Coll Cardiol. 2021 Mar 23. pii: S0735-1097(21)00202-3. [Epub ahead of print]77(11): 1381-1392

Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial.

Milton Packer, Stefan D Anker, Javed Butler, Gerasimos Filippatos, Joao Pedro Ferreira, Stuart J Pocock, Naveed Sattar, Martina Brueckmann, Waheed Jamal, Daniel Cotton, Tomoko Iwata, Faiez Zannad, .

  BACKGROUND: Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention.OBJECTIVES: This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload.
METHODS: This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment.
RESULTS: Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p < 0.001). When compared with placebo, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure, and improved health status and functional class. Yet despite the predisposition of patients with recent volume overload to fluid retention, the magnitude of these benefits (even after 1 month of treatment) was not more marked in patients with recent volume overload (interaction p values > 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients.
CONCLUSIONS: Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Keywords:  SGLT2 inhibitors; diuretic agent; heart failure

DOI:  https://doi.org/10.1016/j.jacc.2021.01.033
Cardiol Res. 2021 Apr;12(2): 91-97

Combination of Linagliptin and Empagliflozin Preserves Cardiac Systolic Function in an Ischemia-Reperfusion Injury Mice With Diabetes Mellitus.

Akihito Ideishi, Yasunori Suematsu, Kohei Tashiro, Hidetaka Morita, Takashi Kuwano, Sayo Tomita, Kanji Nakai, Shin-Ichiro Miura.

  Background: Sodium-glucose co-transporter 2 inhibitor (SGLT2i) and dipeptidyl peptidase 4 inhibitor (DPP4i) are oral hypoglycemic agents. Although SGLT2i has been shown having the beneficial effects on heart failure in basic and clinical studies, the combined effects of SGLT2i and DPP4i have not been established well. We investigated the effects of SGLT2i and DPP4i against diabetes mice model of myocardial ischemia-reperfusion injury.Methods: Streptozotocin-induced diabetic C57BL/6J mice were divided into control (vehicle), empagliflozin (30 mg/kg/day), linagliptin (3 mg/kg/day) and combination (30 mg/kg/day and 3 mg/kg/day, respectively) groups. After 7 days of drug administration, 30 min of myocardial ischemia was performed. We investigated body weight, heart weight, blood glucose, and cardiac functions by pressure-volume Millar catheter followed by 28 days of additional drug administration.
Results: Blood glucose levels, body weight, and heart weight were not significantly different between the groups. In Millar catheter analysis, left ventricular volume at the peak left ventricular ejection rate which is one of the cardiac systolic parameters in combination group was significantly preserved than that in control (P = 0.036). The cardiac index in the combination group tended to be preserved compared to that in the control (P = 0.06). The pathological fibrotic area in the left ventricle in the combination group also tended to be smaller (P = 0.08).
Conclusions: Combination therapy with linagliptin and empagliflozin preserved cardiac systolic function on the diabetes mice model of myocardial ischemia-reperfusion injury independent of blood glucose levels.

Keywords:  Cardiac systolic function; Diabetes mellitus; Empagliflozin; Linagliptin; Myocardial reperfusion injury

DOI:  https://doi.org/10.14740/cr1194