bims-hafaim 2024-02-11 papers

Issue of 2024–02–11
five papers selected by
Kyle McCommis, Saint Louis University

J Cell Physiol. 2024 Feb 03.

Nrf2 prevents diabetic cardiomyopathy via antioxidant effect and normalization of glucose and lipid metabolism in the heart.

Ge Yang, Qihe Zhang, Chao Dong, Guowen Hou, Jinjie Li, Xin Jiang, Ying Xin.

Metabolic disorders and oxidative stress are the main causes of diabetic cardiomyopathy. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exerts a powerful antioxidant effect and prevents the progression of diabetic cardiomyopathy. However, the mechanism of its cardiac protection and direct action on cardiomyocytes are not well understood. Here, we investigated in a cardiomyocyte-restricted Nrf2 transgenic mice (Nrf2-TG) the direct effect of Nrf2 on cardiomyocytes in DCM and its mechanism. In this study, cardiomyocyte-restricted Nrf2 transgenic mice (Nrf2-TG) were used to directly observe whether cardiomyocyte-specific overexpression of Nrf2 can prevent diabetic cardiomyopathy and correct glucose and lipid metabolism disorders in the heart. Compared to wild-type mice, Nrf2-TG mice showed resistance to diabetic cardiomyopathy in a streptozotocin-induced type 1 diabetes mouse model. This was primarily manifested as improved echocardiography results as well as reduced myocardial fibrosis, cardiac inflammation, and oxidative stress. These results showed that Nrf2 can directly act on cardiomyocytes to exert a cardioprotective role. Mechanistically, the cardioprotective effects of Nrf2 depend on its antioxidation activity, partially through improving glucose and lipid metabolism by directly targeting lipid metabolic pathway of AMPK/Sirt1/PGC-1α activation via upstream genes of sestrin2 and LKB1, and indirectly enabling AKT/GSK-3β/HK-Ⅱ activity via AMPK mediated p70S6K inhibition.

Keywords: Nrf2; diabetic cardiomyopathy; glucose metabolic disorder; lipid metabolic disorder; oxidative stress

DOI: https://doi.org/10.1002/jcp.31149

J Mol Cell Cardiol. 2024 Feb;pii: S0022-2828(23)00197-9. [Epub ahead of print]187 101-117

The alpha-1A adrenergic receptor regulates mitochondrial oxidative metabolism in the mouse heart.

Peyton B Sandroni, Melissa A Schroder, Hunter T Hawkins, Julian D Bailon, Wei Huang, James T Hagen, McLane Montgomery, Seok J Hong, Andrew L Chin, Jiandong Zhang, Manoj C Rodrigo, Boa Kim, Paul C Simpson, Jonathan C Schisler, Jessica M Ellis, Kelsey H Fisher-Wellman, Brian C Jensen.

AIMS: The sympathetic nervous system regulates numerous critical aspects of mitochondrial function in the heart through activation of adrenergic receptors (ARs) on cardiomyocytes. Mounting evidence suggests that α1-ARs, particularly the α1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic β-AR activation by shared ligands. The mechanisms underlying these adaptive effects remain unclear. Here, we tested the hypothesis that α1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in both the uninjured and infarcted heart.
METHODS: We used high resolution respirometry, fatty acid oxidation (FAO) enzyme assays, substrate-specific electron transport chain (ETC) enzyme assays, transmission electron microscopy (TEM) and proteomics to characterize mitochondrial function comprehensively in the uninjured hearts of wild type and α1A-AR knockout mice and defined the effects of chronic β-AR activation and myocardial infarction on selected mitochondrial functions.
RESULTS: We found that isolated cardiac mitochondria from α1A-KO mice had deficits in fatty acid-dependent respiration, FAO, and ETC enzyme activity. TEM revealed abnormalities of mitochondrial morphology characteristic of these functional deficits. The selective α1A-AR agonist A61603 enhanced fatty-acid dependent respiration, fatty acid oxidation, and ETC enzyme activity in isolated cardiac mitochondria. The β-AR agonist isoproterenol enhanced oxidative stress in vitro and this adverse effect was mitigated by A61603. A61603 enhanced ETC Complex I activity and protected contractile function following myocardial infarction.
CONCLUSIONS: Collectively, these novel findings position α1A-ARs as critical regulators of cardiomyocyte metabolism in the basal state and suggest that metabolic mechanisms may underlie the protective effects of α1A-AR activation in the failing heart.

Keywords: Adrenergic; Alpha; Basal metabolism; Heart; Lipid metabolism; Mitochondria; Oxidative phosphorylation; Receptors

DOI: https://doi.org/10.1016/j.yjmcc.2023.12.003

Diabetes Obes Metab. 2024 Feb 05.

Uric acid-lowering effects of sodium-glucose cotransporter 2 inhibitors for preventing cardiovascular events and mortality: A systematic review and meta-analysis.

A Diallo, M F Diallo, M Carlos-Bolumbu, F Galtier.

BACKGROUND: To evaluate the effect of a 1 mg/dl reduction in uric acid (UA) on cardiovascular events and mortality in patients treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors.
RESEARCH DESIGN AND METHODS: We performed a systematic review of the MEDLINE and EMBASE databases searched up to 30 June 2023 (PROSPERO, CRD42022355479) to identify large-scale SGLT2 inhibitor trials. Random-effects meta-analyses were used to pool the estimates.
RESULTS: In total, five SGLT2 inhibitor trials (31 535 patients, 54% with heart failure) were analysed. Over a median follow-up of 2.2 years, the mean reduction in UA was -0.79 mg/dl (95% confidence interval (CI), -1.03 to -0.54). Every 1 mg/dl reduction in UA was associated with a significantly lower risk of a composite of cardiovascular death and hospitalization for heart failure [hazard ratio, 0.64 (95% CI, 0.46-0.88)] and hospitalization for heart failure (0.68; 95% CI, 0.62-0.74), with a similar risk of mortality.
CONCLUSIONS: SGLT2 inhibitors reduced UA levels and cardiovascular events independently of heart failure status.

Keywords: heart failure; mortality; sodium-glucose cotransporter 2 inhibitors; uric acid

DOI: https://doi.org/10.1111/dom.15483

NEJM Evid. 2024 Feb;3(2): EVIDoa2300286

Dapagliflozin in Myocardial Infarction without Diabetes or Heart Failure.

Dapagliflozin in Myocardial InfarctionA total of 4017 patients with acute myocardial infarction, but no diabetes or chronic heart failure, were randomly assigned 10 mg of dapagliflozin or placebo. The primary outcome was a composite of death, hospitalization for heart failure, and five cardiometabolic outcomes analyzed using the win ratio method. There were significantly more wins for dapagliflozin than for placebo (win ratio, 1.34; 95% confidence interval, 1.20 to 1.50), which was driven by the cardiometabolic outcomes. The composite of time to cardiovascular death/hospitalization for heart failure was not different between the two groups.

DOI: https://doi.org/10.1056/EVIDoa2300286

Front Cardiovasc Med. 2024 ;11 1293901

Circulating ketone bodies and mortality in heart failure: a community cohort study.

Rebecca O Oyetoro, Katherine M Conners, Jungnam Joo, Sarah Turecamo, Maureen Sampson, Anna Wolska, Alan T Remaley, James D Otvos, Margery A Connelly, Nicholas B Larson, Suzette J Bielinski, Maryam Hashemian, Joseph J Shearer, Véronique L Roger.

Background: The relationship between ketone bodies (KB) and mortality in patients with heart failure (HF) syndrome has not been well established.
Objectives: The aim of this study is to assess the distribution of KB in HF, identify clinical correlates, and examine the associations between plasma KB and all-cause mortality in a population-based HF cohort.
Methods: The plasma KB levels were measured by nuclear magnetic resonance spectroscopy. Multivariable linear regression was used to examine associations between clinical correlates and KB levels. Proportional hazard regression was employed to examine associations between KB (represented as both continuous and categorical variables) and mortality, with adjustment for several clinical covariates.
Results: Among the 1,382 HF patients with KB measurements, the median (IQR) age was 78 (68, 84) and 52% were men. The median (IQR) KB was found to be 180 (134, 308) μM. Higher KB levels were associated with advanced HF (NYHA class III-IV) and higher NT-proBNP levels (both P < 0.001). The median follow-up was 13.9 years, and the 5-year mortality rate was 51.8% [95% confidence interval (CI): 49.1%-54.4%]. The risk of death increased when KB levels were higher (HRhigh vs. low group 1.23; 95% CI: 1.05-1.44), independently of a validated clinical risk score. The association between higher KB and mortality differed by ejection fraction (EF) and was noticeably stronger among patients with preserved EF.
Conclusions: Most patients with HF exhibited KB levels that were consistent with those found in healthy adults. Elevated levels of KB were observed in patients with advanced HF. Higher KB levels were found to be associated with an increased risk of death, particularly in patients with preserved EF.

Keywords: biomarkers; epidemiology; heart failure; ketone bodies; mortality

DOI: https://doi.org/10.3389/fcvm.2024.1293901