bims-hafaim 2021-08-15 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021–08–15
eight papers selected by
Kyle McCommis, Saint Louis University

Cardiomyocyte peroxisome proliferator-activated receptor α is essential for energy metabolism and extracellular matrix homeostasis during pressure overload-induced cardiac remodeling.
NAD+ Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy.
Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice.
Role of metabolomics in identifying cardiac hypertrophy: an overview of the past 20 years of development and future perspective.
Remodeling after myocardial infarction and effects of heart failure treatment investigated by hyperpolarized [1-13 C]pyruvate magnetic resonance spectroscopy.
Effects of 17-AAG on the RIP1/RIP3/MLKL pathway during the development of heart failure following myocardial infarction in rats.
Empagliflozin in Heart Failure With Predicted Preserved Versus Reduced Ejection Fraction: Data From the EMPA-REG OUTCOME Trial.
atg7-Based Autophagy Activation Reverses Doxorubicin-Induced Cardiotoxicity.

Acta Pharmacol Sin. 2021 Aug 10.

Cardiomyocyte peroxisome proliferator-activated receptor α is essential for energy metabolism and extracellular matrix homeostasis during pressure overload-induced cardiac remodeling.

Xia Wang, Xin-Xin Zhu, Shi-Yu Jiao, Dan Qi, Bao-Qi Yu, Guo-Min Xie, Ye Liu, Yan-Ting Song, Qing Xu, Qing-Bo Xu, Frank J Gonzalez, Jie Du, Xiao-Min Wang, Ai-Juan Qu.

  Peroxisome proliferator-activated receptor α (PPARα), a ligand-activated nuclear receptor critical for systemic lipid homeostasis, has been shown closely related to cardiac remodeling. However, the roles of cardiomyocyte PPARα in pressure overload-induced cardiac remodeling remains unclear because of lacking a cardiomyocyte-specific Ppara-deficient (PparaΔCM) mouse model. This study aimed to determine the specific role of cardiomyocyte PPARα in transverse aortic constriction (TAC)-induced cardiac remodeling using an inducible PparaΔCM mouse model. PparaΔCM and Pparafl/fl mice were randomly subjected to sham or TAC for 2 weeks. Cardiomyocyte PPARα deficiency accelerated TAC-induced cardiac hypertrophy and fibrosis. Transcriptome analysis showed that genes related to fatty acid metabolism were dramatically downregulated, but genes critical for glycolysis were markedly upregulated in PparaΔCM hearts. Moreover, the hypertrophy-related genes, including genes involved in extracellular matrix (ECM) remodeling, cell adhesion, and cell migration, were upregulated in hypertrophic PparaΔCM hearts. Western blot analyses demonstrated an increased HIF1α protein level in hypertrophic PparaΔCM hearts. PET/CT analyses showed an enhanced glucose uptake in hypertrophic PparaΔCM hearts. Bioenergetic analyses further revealed that both basal and maximal oxygen consumption rates and ATP production were significantly increased in hypertrophic Pparafl/fl hearts; however, these increases were markedly blunted in PparaΔCM hearts. In contrast, hypertrophic PparaΔCM hearts exhibited enhanced extracellular acidification rate (ECAR) capacity, as reflected by increased basal ECAR and glycolysis but decreased glycolytic reserve. These results suggest that cardiomyocyte PPARα is crucial for the homeostasis of both energy metabolism and ECM during TAC-induced cardiac remodeling, thus providing new insights into potential therapeutics of cardiac remodeling-related diseases.

Keywords:  PPARα; cardiac remodeling; fatty acid metabolism; fibrosis; glycolysis; lipid metabolism

DOI:  https://doi.org/10.1038/s41401-021-00743-z
Circ Heart Fail. 2021 Aug 10. CIRCHEARTFAILURE120008170

NAD+ Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy.

Ying Ann Chiao, Akash Deep Chakraborty, Christine M Light, Rong Tian, Junichi Sadoshima, Xiaojian Shi, Haiwei Gu, Chi Fung Lee.

   BACKGROUND: Diabetes is a risk factor for heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with nicotinamide adenine dinucleotide (NAD+) redox imbalance; however, the hypothesis that NAD+ redox imbalance causes diabetic cardiomyopathy has not been tested. This investigation used mouse models with altered NAD+ redox balance to test this hypothesis.
METHODS: Diabetic stress was induced in mice by streptozotocin. Cardiac function was measured by echocardiography. Heart and plasma samples were collected for biochemical, histological, and molecular analyses. Two mouse models with altered NAD+ redox states (1, Ndufs4 [NADH:ubiquinone oxidoreductase subunit S4] knockout, cKO, and 2, NAMPT [nicotinamide phosphoribosyltranferase] transgenic mice, NMAPT) were used.
RESULTS: Diabetic stress caused cardiac dysfunction and lowered NAD+/NADH ratio (oxidized/reduced ratio of nicotinamide adenine dinucleotide) in wild-type mice. Mice with lowered cardiac NAD+/NADH ratio without baseline dysfunction, cKO mice, were challenged with chronic diabetic stress. NAD+ redox imbalance in cKO hearts exacerbated systolic (fractional shortening: 27.6% versus 36.9% at 4 weeks, male cohort P<0.05), and diastolic dysfunction (early-to-late ratio of peak diastolic velocity: 0.99 versus 1.20, P<0.05) of diabetic mice in both sexes. Collagen levels and transcripts of fibrosis and extracellular matrix-dependent pathways did not show changes in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was due to cardiomyocyte dysfunction. NAD+ redox imbalance promoted superoxide dismutase 2 acetylation, protein oxidation, troponin I S150 phosphorylation, and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD+ levels by NAMPT normalized NAD+ redox balance, alleviated cardiac dysfunction (fractional shortening: 40.2% versus 24.8% in cKO:NAMPT versus cKO, P<0.05; early-to-late ratio of peak diastolic velocity: 1.32 versus 1.04, P<0.05), and reversed pathogenic mechanisms in diabetic mice.
CONCLUSIONS: Our results show that NAD+ redox imbalance to regulate acetylation and phosphorylation is a critical mediator of the progression of diabetic cardiomyopathy and suggest the therapeutic potential for diabetic cardiomyopathy by harnessing NAD+ metabolism.

Keywords:  NAD+ redox imbalance; cardiomyopathy; diabetes; heart failure; risk factor

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.120.008170
Redox Biol. 2021 Jul 30. pii: S2213-2317(21)00247-0. [Epub ahead of print]46 102088

Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice.

Dongqi An, Qingchun Zeng, Peijian Zhang, Zhuang Ma, Hao Zhang, Zuheng Liu, Jiaying Li, Hao Ren, Dingli Xu.

  Increasing evidence indicates the involvement of myocardial oxidative injury and mitochondrial dysfunction in the pathophysiology of heart failure (HF). Alpha-ketoglutarate (AKG) is an intermediate metabolite of the tricarboxylic acid (TCA) cycle that participates in different cellular metabolic and regulatory pathways. The circulating concentration of AKG was found to decrease with ageing and is elevated after acute exercise and resistance exercise and in HF. Recent studies in experimental models have shown that dietary AKG reduces reactive oxygen species (ROS) production and systemic inflammatory cytokine levels, regulates metabolism, extends lifespan and delays the occurrence of age-related decline. However, the effects of AKG on HF remain unclear. In the present study, we explored the effects of AKG on left ventricular (LV) systolic function, the myocardial ROS content and mitophagy in mice with transverse aortic constriction (TAC). AKG supplementation inhibited pressure overload-induced myocardial hypertrophy and fibrosis and improved cardiac systolic dysfunction; in vitro, AKG decreased the Ang II-induced upregulation of β-MHC and ANP, reduced ROS production and cardiomyocyte apoptosis, and repaired Ang II-mediated injury to the mitochondrial membrane potential (MMP). These benefits of AKG in the TAC mice may have been obtained by enhanced mitophagy, which cleared damaged mitochondria. In summary, our study suggests that AKG improves myocardial hypertrophy remodelling, fibrosis and LV systolic dysfunction in the pressure-overloaded heart by promoting mitophagy to clear damaged mitochondria and reduce ROS production; thus, AKG may have therapeutic potential for HF.

Keywords:  Alpha-ketoglutarate; Cardiac insufficiency; Mitophagy; Myocardial hypertrophy; Transverse aortic constriction

DOI:  https://doi.org/10.1016/j.redox.2021.102088
Expert Rev Mol Med. 2021 Aug 11. 23 e8

Role of metabolomics in identifying cardiac hypertrophy: an overview of the past 20 years of development and future perspective.

Sachendra Pratap Singh, Rishi Sethi, Shailendra Kumar Saxena, Ashish Gupta.

  Cardiac hypertrophy (CH) is an augmentation of either the right ventricular or the left ventricular mass in order to compensate for the increase of work load on the heart. Metabolic abnormalities lead to histological changes of cardiac myocytes and turn into CH. The molecular mechanisms that lead to initiate CH have been of widespread concern, hence the development of the new field of research, metabolomics: one 'omics' approach that can reveal comprehensive information of the paradigm shift of metabolic pathways network in contrast to individual enzymatic reaction-based metabolites, have attempted and until now only 19 studies have been conducted using experimental animal and human specimens. Nuclear magnetic resonance spectroscopy and mass spectrometry-based metabolomics studies have found that CH is a metabolic disease and is mainly linked to the harmonic imbalance of glycolysis, citric acid cycle, amino acids and lipid metabolism. The current review will summarise the main outcomes of the above mentioned 19 studies that have expanded our understanding of the molecular mechanisms that may lead to CH and eventually to heart failure.

Keywords:  Cardiac hypertrophy; NMR spectroscopy; left ventricle hypertrophy; mass spectrometry; metabolomics; right ventricle hypertrophy

DOI:  https://doi.org/10.1017/erm.2021.12
Magn Reson Med. 2021 Aug 11.

Remodeling after myocardial infarction and effects of heart failure treatment investigated by hyperpolarized [1-13 C]pyruvate magnetic resonance spectroscopy.

Rasmus Stilling Tougaard, Christoffer Laustsen, Thomas Ravn Lassen, Haiyun Qi, Jakob Lykke Lindhardt, Marie Schroeder, Nichlas Riise Jespersen, Esben Søvsø Szocska Hansen, Steffen Ringgaard, Hans Erik Bøtker, Won Yong Kim, Hans Stødkilde-Jørgensen, Henrik Wiggers.

   PURPOSE: Hyperpolarized [1-13 C]pyruvate MRS can measure cardiac metabolism in vivo. We investigated whether [1-13 C]pyruvate MRS could predict left ventricular remodeling following myocardial infarction (MI), long-term left ventricular effects of heart failure medication, and could identify responders to treatment.
METHODS: Thirty-five rats were scanned with hyperpolarized [1-13 C]pyruvate MRS 3 days after MI or sham surgery. The animals were re-examined after 30 days of therapy with β-blockers and ACE-inhibitors (active group, n = 12), placebo treatment (placebo group, n = 13) or no treatment (sham group, n = 10). Furthermore, heart tissue mitochondrial respiratory capacity was assessed by high-resolution respirometry. Metabolic results were compared between groups, over time and correlated to functional MR data at each time point.
RESULTS: At 30 ± 0.5 days post MI, left ventricular ejection fraction (LVEF) differed between groups (sham, 77% ± 1%; placebo, 52% ± 3%; active, 63% ± 2%, P < .001). Cardiac metabolism, measured by both hyperpolarized [1-13 C]pyruvate MRS and respirometry, neither differed between groups nor between baseline and follow-up. Three days post MI, low bicarbonate + CO2 /pyruvate ratio was associated with low LVEF. At follow-up, in the active group, a poor recovery of LVEF was associated with high bicarbonate + CO2 /pyruvate ratio, as measured by hyperpolarized MRS.
CONCLUSION: In a rat model of moderate heart failure, medical treatment improved function, but did not on average influence [1-13 C]pyruvate flux as measured by MRS; however, responders to heart failure medication had reduced capacity for carbohydrate metabolism.

Keywords:  MRS; animal models of human disease; heart failure; metabolism; myocardial infarction; remodeling

DOI:  https://doi.org/10.1002/mrm.28964
J Pharmacol Sci. 2021 Oct;pii: S1347-8613(21)00065-7. [Epub ahead of print]147(2): 192-199

Effects of 17-AAG on the RIP1/RIP3/MLKL pathway during the development of heart failure following myocardial infarction in rats.

Tetsuro Marunouchi, Takumi Ito, Sumika Onda, Lina Kyo, Kirara Takahashi, Manami Uchida, Emi Yano, Kouichi Tanonaka.

  In a previous study, we suggested that the Hsp90 inhibitor 17-AAG prevents cardiac dysfunction in the failing heart following myocardial infarction in rats. Although it is assumed that the RIP1/RIP3/MLKL necroptotic pathway, which comprises client proteins for Hsp90, is involved; however, the relationship between the cardioprotective effects of 17-AAG and the activity of the cardiac RIP1/RIP3/MLKL necrosome-associated proteins in the failing heart following myocardial infarction remained unclear. Therefore, the levels of phosphorylated MLKL after myocardial infarction with or without Hsp90 inhibitor treatment were measured. Myocardial infarction was induced by ligation of the coronary artery (CAL) in Wistar rats. 17-AAG was injected from the 2nd to the 8th week after myocardial infarction. The administration of 17-AAG attenuated the cardiac dysfunction, hypertrophy, and fibrosis at the 8th week after CAL, simultaneously lessening the increases in the expression and phosphorylation levels of RIP1, RIP3, and MLKL in the area of the left ventricular muscle without infarct. These results indicate that the activation of the RIP1/RIP3/MLKL pathway is a common event in the development of chronic heart failure. Furthermore, our findings suggest that the effects of 17-AAG treatment on the improvement of cardiac function in rats after myocardial infarction is related to the attenuation of this RIP1/RIP3/MLKL pathway.

Keywords:  Heart failure; Hsp90 inhibitor; MLKL; Myocardial infarction; RIP

DOI:  https://doi.org/10.1016/j.jphs.2021.06.009
J Card Fail. 2021 Aug;pii: S1071-9164(21)00202-5. [Epub ahead of print]27(8): 888-895

Empagliflozin in Heart Failure With Predicted Preserved Versus Reduced Ejection Fraction: Data From the EMPA-REG OUTCOME Trial.

Gianluigi Savarese, Alicia Uijl, Lars H Lund, Stefan D Anker, Folkert Asselbergs, David Fitchett, Silvio E Inzucchi, Stefan Koudstaal, Anne Pernille Ofstad, Benedikt Schrage, Ola Vedin, Christoph Wanner, Faiez Zannad, Isabella Zwiener, Javed Butler.

   BACKGROUND: In the EMPA-REG OUTCOME trial, ejection fraction (EF) data were not collected. In the subpopulation with heart failure (HF), we applied a new predictive model for EF to determine the effects of empagliflozin in HF with predicted reduced (HFrEF) vs preserved (HFpEF) EF vs no HF.
METHODS AND RESULTS: We applied a validated EF predictive model based on patient baseline characteristics and treatments to categorize patients with HF as being likely to have HF with mid-range EF (HFmrEF)/HFrEF (EF <50%) or HFpEF (EF ≥50%). Cox regression was used to assess the effect of empagliflozin vs placebo on cardiovascular death/HF hospitalization (HHF), cardiovascular and all-cause mortality, and HHF in patients with predicted HFpEF, HFmrEF/HFrEF and no HF. Of 7001 EMPA-REG OUTCOME patients with data available for this analysis, 6314 (90%) had no history of HF. Of the 687 with history of HF, 479 (69.7%) were predicted to have HFmrEF/HFrEF and 208 (30.3%) to have HFpEF. Empagliflozin's treatment effect was consistent in predicted HFpEF, HFmrEF/HFrEF and no-HF for each outcome (HR [95% CI] for the primary outcome 0.60 [0.31-1.17], 0.79 [0.51-1.23], and 0.63 [0.50-0.78], respectively; P interaction = 0.62).
CONCLUSIONS: In EMPA-REG OUTCOME, one-third of the patients with HF had predicted HFpEF. The benefits of empagliflozin on HF and mortality outcomes were consistent in nonHF, predicted HFpEF and HFmrEF/HFrEF.

Keywords:  EMPA-REG OUTCOME; Heart failure with preserved ejection fraction; empagliflozin; heart failure with mid-range ejection fraction; heart failure with mildly reduced ejection fraction; heart failure with reduced ejection fraction; type 2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.cardfail.2021.05.012
Circ Res. 2021 Aug 13.

atg7-Based Autophagy Activation Reverses Doxorubicin-Induced Cardiotoxicity.

Yong Wang, Xiaoguang Lu, Xiaoping Wang, Qi Qiu, Ping Zhu, Lin Ma, Xiao Ma, Joerg Herrmann, Xueying Lin, Wei Wang, Xiaolei Xu.

Rationale: Anthracycline-induced cardiotoxicity (AIC) is a major side effect that limits the use of anthracyclines as effective chemotherapeutics. No mechanism-based therapy is available when cardiac function deteriorates.Objective: We aim to elucidate the dynamic autophagic defects in AIC, and to identify a mechanism-based therapy via both genetic and pharmacological studies. Methods and Results: Through phenotyping an adult AIC (aAIC) zebrafish model, we detected a biphasic response in autophagy: activation in the early stage and suppression in the later phase that is characterized by a decline in cardiac function. We conducted conditional genetic studies with atg7, which encodes a rate-limiting autophagy core protein, and found that atg7 overexpression (OE) leads to therapeutic effects in the late phase but deleterious effects in the early phase of aAIC. We then assessed the therapeutic effects of 37 FDA-approved autophagy activators (FAAs) using an embryonic AIC (eAIC) zebrafish model and identified spironolactone, pravastatin, and minoxidil as top-ranking drugs. We demonstrated the therapeutic efficacy of these FAAs in the aAIC model and confirmed that these drugs exert therapeutic effects in the late phase but not in the early AIC phase. Finally, we demonstrated that the time-dependent therapeutic effects are conserved in a mouse AIC model and that spironolactone and rapamycin activated autophagy in an Atg7-dependent fashion. Conclusions: Our findings suggest that atg7-based autophagy activation is an effective therapeutic avenue to reversing the decline in cardiac function in AIC, highlighting the time dependent nature of autophagy-based therapy.

DOI: https://doi.org/10.1161/CIRCRESAHA.121.319104