bims-hafaim 2023-09-10 papers

Issue of 2023‒09‒10
four papers selected by
Kyle McCommis, Saint Louis University

J Clin Invest. 2023 Sep 05. pii: e169399. [Epub ahead of print]

Reducing branched-chain amino acids improves cardiac stress response in mice by decreasing histone H3K23 propionylation.

Zhi Yang, Minzhen He, Julianne Austin, Danish Sayed, Maha Abdellatif.

Identifying branched-chain amino acid (BCAA) oxidation enzymes in the nucleus led us to predict that they are a source of propionyl-CoA that are utilized for histone propionylation and, thereby, regulate gene expression. To investigate the effects of BCAA on the development of cardiac hypertrophy and failure, we applied pressure overload on the heart in mice maintained on a diet with standard levels of BCAA (BCAA-control) versus a BCAA-free diet. The former was associated with an increase in histone H3K23-propionyl (H3K23Pr) at the promoters of upregulated genes [e.g., cell signaling and extracellular matrix genes] and a decrease at the promoters of downregulated genes [e.g., electron transfer complex (ETC I-V) and metabolic genes]. Intriguingly, the BCAA-free diet tempered the increases in promoter-H3K23Pr, thus, reducing collagen gene expression and fibrosis during cardiac hypertrophy. Conversely, the BCAA-free diet inhibited the reductions in promoter-H3K23Pr and abolished the downregulation of ETC I-V subunits, enhanced mitochondrial respiration, and curbed progression of cardiac hypertrophy. Thus, lowering the intake of BCAA reduces pressure overload-induced changes in histone propionylation-dependent gene expression in the heart, which retards the development of cardiomyopathy.

Keywords: Cardiology; Cardiovascular disease; Epigenetics; Metabolism; Transcription

DOI: https://doi.org/10.1172/JCI169399

Cardiovasc Diabetol. 2023 09 02. 22(1): 235

Left ventricular remodeling response to SGLT2 inhibitors in heart failure: an updated meta-analysis of randomized controlled studies.

Erberto Carluccio, Paolo Biagioli, Gianpaolo Reboldi, Anna Mengoni, Rosanna Lauciello, Cinzia Zuchi, Sandra D'Addario, Giuliana Bardelli, Giuseppe Ambrosio.

BACKGROUND: Randomized controlled trials (RCTs) reported contrasting results about reverse left ventricular remodeling (LVR) after sodium-glucose co-transporter-2 inhibitors (SGLT2i) therapy in patients with heart failure (HF).METHODS AND RESULTS: We performed a metanalysis of RCTs of SGLT2i administration in HF outpatients published until June 2022 searching four electronic databases. The protocol has been published in PROSPERO. Primary LVR outcome was change in absolute LV end-diastolic (LVEDV) and end-systolic volume (LVESV) from baseline to study endpoint. Secondary outcomes included changes in LVEDV and LVESV indexed to body surface area, LV Mass index (LVMi), LV ejection fraction (LVEF), and N-terminal pro-B-type natriuretic peptide (NTproBNP). Mean differences (MDs) with 95% CIs were pooled. A total of 9 RCTs (1385 patients) were analyzed. All of them reported data on LVEF. Six trials reported data on LVESV and LVEDV (n = 951); LVMi was available in 640. SGLT2i treatment significantly reduced LVEDV [MD= -10.59 ml (-17.27; -3.91), P = 0.0019], LVESV [MD= -8.80 ml (-16.91; -0.694), P = 0.0334], and LVMI [MD= -5.34 gr/m2 (-9.76; -0.922), P = 0.0178], while LVEF significantly increased [MD = + 1.98% (0.67; 0.306), P = 0.0031]. By subgroup analysis, the beneficial effects of SGLT2i on LVEF did not differ by imaging method used, time to follow-up re-evaluation, or HF phenotype. Reduction in LV volumes tended to be greater in HF with reduced EF (HFrEF) than in those with preserved EF (HFpEF), while the opposite was observed for LVMi.
CONCLUSIONS: Treatment with SGLT2i significantly reversed cardiac volumes, improving LV systolic function and LV mass, particularly in HFrEF patients.

Keywords: Cardiac magnetic resonance imaging; Echocardiography, Cardiac remodelling; HFrEF, HFpEF; SGLT2i

DOI: https://doi.org/10.1186/s12933-023-01970-w

Biol Direct. 2023 Sep 04. 18(1): 54

Perilipin 5 deficiency aggravates cardiac hypertrophy by stimulating lactate production in leptin-deficient mice.

Lele Jian, Xing Gao, Chao Wang, Xiao Sun, Yuqiao Xu, Ruili Han, Yuying Wang, Shenhui Xu, Lan Ding, Jingjun Zhou, Yu Gu, Yuanlin Zhao, Ying Yang, Yuan Yuan, Jing Ye, Lijun Zhang.

BACKGROUND: Perilipin 5 (Plin5) is well known to maintain the stability of intracellular lipid droplets (LDs) and regulate fatty acid metabolism in oxidative tissues. It is highly expressed in the heart, but its roles have yet to be fully elucidated.METHODS: Plin5-deficient mice and Plin5/leptin-double-knockout mice were produced, and their histological structures and myocardial functions were observed. Critical proteins related to fatty acid and glucose metabolism were measured in heart tissues, neonatal mouse cardiomyocytes and Plin5-overexpressing H9C2 cells. 2-NBDG was employed to detect glucose uptake. The mitochondria and lipid contents were observed by MitoTracker and BODIPY 493/503 staining in neonatal mouse cardiomyocytes.
RESULTS: Plin5 deficiency impaired glucose utilization and caused insulin resistance in mouse cardiomyocytes, particularly in the presence of fatty acids (FAs). Additionally, Plin5 deficiency increased the NADH content and elevated the expression of lactate dehydrogenase (LDHA) in cardiomyocytes, which resulted in increased lactate production. Moreover, when fatty acid oxidation was blocked by etomoxir or LDHA was inhibited by GSK2837808A in Plin5-deficient cardiomyocytes, glucose utilization was improved. Leptin-deficient mice exhibited myocardial hypertrophy, insulin resistance and altered substrate utilization, and Plin5 deficiency exacerbated myocardial hypertrophy in leptin-deficient mice.
CONCLUSION: Our results demonstrated that Plin5 plays a critical role in coordinating fatty acid and glucose oxidation in cardiomyocytes, providing a potential target for the treatment of metabolic disorders in the heart.

Keywords: Glucose utilization; Insulin resistance; Lactate; Myocardial hypertrophy; Perilipin 5

DOI: https://doi.org/10.1186/s13062-023-00411-8

Eur Heart J. 2023 Sep 07. pii: ehad389. [Epub ahead of print]

Mechanisms of benefits of sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction.

Arjun K Pandey, Deepak L Bhatt, Avinash Pandey, Nikolaus Marx, Francesco Cosentino, Ambarish Pandey, Subodh Verma.

For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF.

Keywords: Heart Failure • SGLT2 Inhibitor • HFpEF • Diabetes Mellitus

DOI: https://doi.org/10.1093/eurheartj/ehad389