bims-hafaim 2022-07-03 papers

Issue of 2022–07–03
four papers selected by
Kyle McCommis, Saint Louis University

Basic Res Cardiol. 2022 Jul 01. 117(1): 33

Prolonged cardiac NR4A2 activation causes dilated cardiomyopathy in mice.

Sadia Ashraf, Heinrich Taegtmeyer, Romain Harmancey.

Transcription factors play a fundamental role in cardiovascular adaptation to stress. Nuclear receptor subfamily 4 group A member 2 (NR4A2; NURR1) is an immediate-early gene and transcription factor with a versatile role throughout many organs. In the adult mammalian heart, and particularly in cardiac myocytes, NR4A2 is strongly up-regulated in response to beta-adrenergic stimulation. The physiologic implications of this increase remain unknown. In this study, we aimed to interrogate the consequences of cardiac NR4A2 up-regulation under normal conditions and in response to pressure overload. In mice, tamoxifen-dependent, cardiomyocyte-restricted overexpression of NR4A2 led to cardiomyocyte hypertrophy, left ventricular dilation, heart failure, and death within 40 days. Chronic NR4A2 induction also precipitated cardiac decompensation during transverse aortic constriction (TAC)-induced pressure overload. Mechanistically, NR4A2 caused adult cardiac myocytes to return to a fetal-like phenotype, with a switch to glycolytic metabolism and disassembly of sarcomeric structures. NR4A2 also re-activated cell cycle progression and stimulated DNA replication and karyokinesis but failed to induce cytokinesis, thereby promoting multinucleation of cardiac myocytes. Activation of cell cycle checkpoints led to induction of an apoptotic response which ultimately resulted in excessive loss of cardiac myocytes and impaired left ventricular contractile function. In summary, myocyte-specific overexpression of NR4A2 in the postnatal mammalian heart results in increased cell cycle re-entry and DNA replication but does not result in cardiac myocyte division. Our findings expose a novel function for the nuclear receptor as a critical regulator in the self-renewal of the cardiac myocyte and heart regeneration.

Keywords: Cardiac regeneration; Cell cycle; Dilated cardiomyopathy; Heart failure; Nuclear receptors

DOI: https://doi.org/10.1007/s00395-022-00942-7

JCI Insight. 2022 Jun 30. pii: e155475. [Epub ahead of print]

UCP2 modulates cardiomyocyte cell cycle activity, acetyl-CoA and histone acetylation in response to moderate hypoxia.

Vagner Oc Rigaud, Clare Zarka, Justin Kurian, Daria Harlamova, Andrea Elia, Nicole Kasatkin, Jaslyn Johnson, Michael Behanan, Lindsay Kraus, Hannah Pepper, Nathaniel W Snyder, Sadia Mohsin, Steven Houser, Mohsin Khan.

Developmental cardiac tissue is regenerative while operating under low oxygen. After birth, ambient oxygen is associated with cardiomyocyte cell cycle exit and regeneration. Likewise, cardiac metabolism undergoes a shift with cardiac maturation. Whether there are common regulators of cardiomyocyte cell cycle linking metabolism to oxygen tension remains unknown. The objective of the study is to determine whether mitochondrial UCP2 is a metabolic oxygen sensor regulating cardiomyocyte cell cycle. Neonatal rat ventricular myocytes (NRVMs) under moderate hypoxia showed increased cell cycle activity and UCP2 expression. NRVMs exhibited a metabolic shift towards glycolysis, reduced citrate synthase, mtDNA, ΔΨm and DNA damage/oxidative stress while loss of UCP2 reversed this phenotype. Next, WT and UCP2KO mice kept under hypoxia for 4 weeks showed significant decline in cardiac function that was more pronounced in UCP2KO animals. Cardiomyocyte cell cycle activity was reduced while fibrosis and DNA damage was significantly increased in UCP2KO animals compared to WT under hypoxia. Mechanistically, UCP2 increased acetyl-CoA levels, histone acetylation and altered chromatin modifiers linking metabolism to cardiomyocyte cell cycle under hypoxia. Here, we show a novel role for mitochondrial UCP2 as an oxygen sensor regulating cardiomyocyte cell cycle activity, acetyl-CoA levels and histone acetylation in response to moderate hypoxia.

Keywords: Cardiology; Cell cycle; Hypoxia; Metabolism; Uncoupling proteins

DOI: https://doi.org/10.1172/jci.insight.155475

Circulation. 2022 Jun 28. 101161CIRCULATIONAHA122059785

Empagliflozin for Heart Failure With Preserved Left Ventricular Ejection Fraction With and Without Diabetes.

EMPEROR-Preserved Trial Committees and Investigators

BACKGROUND: Empagliflozin improves outcomes in patients with heart failure with a preserved ejection fraction, but whether the effects are consistent in patients with and without diabetes remains to be elucidated.
METHODS: Patients with class II through IV heart failure and a left ventricular ejection fraction >40% were randomized to receive empagliflozin 10 mg or placebo in addition to usual therapy. We undertook a prespecified analysis comparing the effects of empagliflozin versus placebo in patients with and without diabetes.
RESULTS: Of the 5988 patients enrolled, 2938 (49%) had diabetes. The risk of the primary outcome (first hospitalization for heart failure or cardiovascular death), total hospitalizations for heart failure, and estimated glomerular filtration rate decline was higher in patients with diabetes. Empagliflozin reduced the rate of the primary outcome irrespective of diabetes status (hazard ratio, 0.79 [95% CI, 0.67, 0.94] for patients with diabetes versus hazard ratio, 0.78 [95% CI, 0.64, 0.95] in patients without diabetes; Pinteraction=0.92). The effect of empagliflozin to reduce total hospitalizations for heart failure was also consistent in patients with and without diabetes. The effect of empagliflozin to attenuate estimated glomerular filtration rate decline during double-blind treatment was also present in patients with and without diabetes, although more pronounced in patients with diabetes (1.77 in diabetes versus 0.98 mL/min per 1.73 m2 in patients without diabetes; Pinteraction=0.01). Across these 3 end points, the effect of empagliflozin did not differ in patients with prediabetes or normoglycemia (33% and 18% of the patient population, respectively). When investigated as a continuous variable, baseline hemoglobin A1c did not modify the effects on the primary outcome (Pinteraction=0.26). There was no increased risk of hypoglycemic events in either subgroup as compared with placebo.
CONCLUSIONS: In patients with heart failure and a preserved ejection fraction enrolled in EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline.
REGISTRATION: URL: https://www.
CLINICALTRIALS: gov; Unique identifier: NCT03057951.

Keywords: death; heart failure; hospitalization; prognosis

DOI: https://doi.org/10.1161/CIRCULATIONAHA.122.059785

Front Mol Biosci. 2022 ;9 823602

β-Hydroxybutyrate in Cardiovascular Diseases : A Minor Metabolite of Great Expectations.

Shao Wei, Liu Binbin, Wu Yuan, Zhang Zhong, Lin Donghai, Huang Caihua.

Despite recent advances in therapies, cardiovascular diseases ( CVDs ) are still the leading cause of mortality worldwide. Previous studies have shown that metabolic perturbations in cardiac energy metabolism are closely associated with the progression of CVDs. As expected, metabolic interventions can be applied to alleviate metabolic impairments and, therefore, can be used to develop therapeutic strategies for CVDs. β-hydroxybutyrate (β-HB) was once known to be a harmful and toxic metabolite leading to ketoacidosis in diabetes. However, the minor metabolite is increasingly recognized as a multifunctional molecular marker in CVDs. Although the protective role of β-HB in cardiovascular disease is controversial, increasing evidence from experimental and clinical research has shown that β-HB can be a "super fuel" and a signaling metabolite with beneficial effects on vascular and cardiac dysfunction. The tremendous potential of β-HB in the treatment of CVDs has attracted many interests of researchers. This study reviews the research progress of β-HB in CVDs and aims to provide a theoretical basis for exploiting the potential of β-HB in cardiovascular therapies.

Keywords: cardiac energy metabolism; cardiovascular diseases; cardiovascular therapies; signaling metabolite; super fuel; β-hydroxybutyrate

DOI: https://doi.org/10.3389/fmolb.2022.823602