bims-hafaim 2023-07-16 papers

Issue of 2023‒07‒16
six papers selected by
Kyle McCommis
Saint Louis University

Eur J Heart Fail. 2023 Jul 11.

Fetal Recapitulation of Nutrient Surplus Signaling by O-GlcNAcylation and the Failing Heart.

The development of the fetal heart is driven by increased glucose uptake and activation of mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF-1α), which drives glycolysis. In contrast, the healthy adult heart is governed by sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK), which promote fatty-acid oxidation and the substantial mitochondrial ATP production required for survival in a high-workload normoxic environment. During cardiac injury, the heart recapitulates the fetal signaling program, which (although adaptive in the short-term) is highly deleterious if sustained for long periods of time. Prolonged increases in glucose uptake in cardiomyocytes under stress leads to increased flux through the hexosamine biosynthesis pathway; its endproduct - uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) - functions as a critical nutrient surplus sensor. UDP-GlcNAc drives the post-translational protein modification known as O-GlcNAcylation, which rapidly and reversibly modifies thousands of intracellular proteins. Both O-GlcNAcylation and phosphorylation act at serine/ threonine residues, but whereas phosphorylation is regulated by hundreds of specific kinases and phosphatases, O-GlcNAcylation is regulated by only two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which adds or removes O-GlcNAc, respectively, from target proteins. Recapitulation of fetal programming in heart failure (regardless of diabetes) is accompanied by marked increases in O-GlcNAcylation, both experimentally and clinically. Heightened O-GlcNAcylation in the heart leads to impaired calcium kinetics and contractile derangements, arrhythmias related to activation of voltage-gated sodium channels and Ca2+ /calmodulin-dependent protein kinase II, mitochondrial dysfunction, and maladaptive hypertrophy, microvascular dysfunction, fibrosis and cardiomyopathy. These deleterious effects can be prevented by suppression of O-GlcNAcylation, which can be achieved experimentally by upregulation of AMPK and SIRT1 or by pharmacological inhibition of OGT or stimulation of OGA. The effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the heart are accompanied by reduced O-GlcNAcylation, and their cytoprotective effects are reportedly abrogated if their action to suppress O-GlcNAcylation is blocked. Such an action may represent one of the many mechanisms by which enhanced AMPK and SIRT1 signaling following SGLT2 inhibition leads to cardiovascular benefits. These observations, taken collectively, suggest that UDP-GlcNAc functions as a critical nutrient surplus sensor (which acting in concert with mTOR and HIF-1α) can promote the development of cardiomyopathy. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ejhf.2972

J Cardiovasc Transl Res. 2023 Jul 14.

From Energy Metabolic Change to Precision Therapy: a Holistic View of Energy Metabolism in Heart Failure.

Jianpei Wen, Chen Chen.

Heart failure (HF) is a complex and multifactorial disease that affects millions of people worldwide. It is characterized by metabolic disturbances of substrates such as glucose, fatty acids (FAs), ketone bodies, and amino acids, which lead to changes in cardiac energy metabolism pathways. These metabolic alterations can directly or indirectly promote myocardial remodeling, thereby accelerating the progression of HF, resulting in a vicious cycle of worsening symptoms, and contributing to the increased hospitalization and mortality among patients with HF. In this review, we summarized the latest researches on energy metabolic profiling in HF and provided the related translational therapeutic strategies for this devastating disease. By taking a holistic approach to understanding energy metabolism changes in HF, we hope to provide comprehensive insights into the pathophysiology of this challenging condition and identify novel precise targets for the development of more effective treatments.

Keywords: Energy metabolism; Heart failure; Metabolic profile; Therapy

DOI: https://doi.org/10.1007/s12265-023-10412-7

J Mol Cell Cardiol. 2023 Jul 12. pii: S0022-2828(23)00110-4. [Epub ahead of print]182 15-24

Metabolic flux in the driver's seat during cardiac health and disease.

E Douglas Lewandowski.

Cardiac function is a dynamic process that must adjust efficiently to the immediate demands of physical state and activity. So too, the metabolic support of cardiac function is a dynamic process that must respond, in time, to the demands of cardiac function and viability. Flux through metabolic pathways provides chemical energy and generates signaling molecules that regulate activity among intracellular compartments to meet these demands. Thus, flux through metabolic pathways provides a dynamic mode of support of cardiomyocytes during physiological and pathophysiological challenges. Any inability of metabolic flux to keep pace with the demands of the cardiomyocyte results in progressive dysfunction that contributes to cardiac disease. Thus, the priority in maintaining and regulating flux through metabolic pathways in the cardiomyocyte cannot be understated. Great potential exists in current efforts to elucidate metabolic mechanisms as therapeutic targets for the diseased heart. As a consequence, detecting metabolic flux in the functioning myocardium of the heart, under normal and diseased conditions, is essential in elucidating the metabolic basis of contractile dysfunction. As a companion to the 2022 ISHR Research Achievement Award lecture, this review examines the use and applications of stable isotope kinetics to quantify metabolic flux through intermediary pathways and the exchange and transport of intermediates across the mitochondrial membrane and sarcolemma of intact functioning hearts in determining how these intracellular events are coordinated to support cardiac function and health. Finally, this work reviews recently demonstrated metabolic defects in diseased hearts and the potential for metabolic alleviation of heart disease.

Keywords: Fatty acids; Glucose; Heart failure; Ischemia/Reperfusion; Isotopes; Metabolism; Mitochondria

DOI: https://doi.org/10.1016/j.yjmcc.2023.07.004

Nat Metab. 2023 Jul 13.

CRAT links cholesterol metabolism to innate immune responses in the heart.

Hua Mao, Aude Angelini, Shengyu Li, Guangyu Wang, Luge Li, Cam Patterson, Xinchun Pi, Liang Xie.

Chronic inflammation is associated with increased risk and poor prognosis of heart failure; however, the precise mechanism that provokes sustained inflammation in the failing heart remains elusive. Here we report that depletion of carnitine acetyltransferase (CRAT) promotes cholesterol catabolism through bile acid synthesis pathway in cardiomyocytes. Intracellular accumulation of bile acid or intermediate, 7α-hydroxyl-3-oxo-4-cholestenoic acid, induces mitochondrial DNA stress and triggers cGAS-STING-dependent type I interferon responses. Furthermore, type I interferon responses elicited by CRAT deficiency substantially increase AIM2 expression and AIM2-dependent inflammasome activation. Genetic deletion of cardiomyocyte CRAT in mice of both sexes results in myocardial inflammation and dilated cardiomyopathy, which can be reversed by combined depletion of caspase-1, cGAS or AIM2. Collectively, we identify a mechanism by which cardiac energy metabolism, cholesterol homeostasis and cardiomyocyte-intrinsic innate immune responses are interconnected via a CRAT-mediated bile acid synthesis pathway, which contributes to chronic myocardial inflammation and heart failure progression.

DOI: https://doi.org/10.1038/s42255-023-00844-5

Metabolism. 2023 Jul 09. pii: S0026-0495(23)00262-7. [Epub ahead of print]146 155658

PRDM16 exerts critical role in myocardial metabolism and energetics in type 2 diabetes induced cardiomyopathy.

Tongtong Hu, Qingqing Wu, Qi Yao, Jiabin Yu, Kebing Jiang, Ying Wan, Qizhu Tang.

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) has increased over the past decades. Diabetic cardiomyopathy (DCM) is the leading cause of death in T2DM patients, however, the mechanism underlying DCM remains largely unknown. Here, we aimed to investigate the role of cardiac PR-domain containing 16 (PRDM16) in T2DM.METHODS: We modeled mice with cardiac-specific deletion of Prdm16 by crossing the floxed Prdm16 mouse model with the cardiomyocyte-specific Cre transgenic mouse. The mice were continuously fed a chow diet or high-fat diet combining with streptozotocin (STZ) for 24 weeks to establish a T2DM model. DB/DB and adequate control mice were given a single intravenous injection of adeno-associated virus 9 (AAV9) carrying cardiac troponin T (cTnT) promoter-driven small hairpin RNA targeting PRDM16 (AAV9-cTnT-shPRDM16) from the retro-orbital venous plexus to knockout Prdm16 in the myocardium. There were at least 12 mice in each group. Mitochondrial morphology and function were detected using transmission electron microscopy, western blot determining the protein level of mitochondrial respiratory chain complex, mitotracker staining and Seahorse XF Cell Mito Stress Test Kit. Untargeted metabolomics analysis and RNA-seq analysis were performed to determine the molecular and metabolic changes associated with Prdm16 deficiency. BODIPY and TUNEL staining were used to detect lipid uptake and apoptosis. Co-immunoprecipitation and ChIP assays were conducted to examine the potential underlying mechanism.
RESULTS: Prdm16 cardiac-specific deficiency accelerated cardiomyopathy and worsened cardiac dysfunction in mice with T2DM, aggravating mitochondrial dysfunction and apoptosis both in vivo and in vitro, while PRDM16 overexpression the deterioration. Prdm16 deficiency also caused cardiac lipid accumulation resulting in metabolic and molecular alterations in T2DM mouse models. Co-IP and luciferase assays confirmed that PRDM16 targeted and regulated the transcriptional activity, expression and interaction of PPAR-α and PGC-1α, while the overexpression of PPAR-α and PGC-1α reversed Prdm16 deficiency-induced cellular dysfunction in T2DM model. Moreover, PRDM16 regulated PPAR-α and PGC-1α and affected mitochondrial function by mainly depending on epigenetic regulation of H3K4me3.
CONCLUSIONS: These findings suggest that PRDM16 exerted its protective role in myocardial lipid metabolism and mitochondrial function in T2DM in a histone lysine methyltransferase activity-dependent manner by regulating PPAR-α and PGC-1α.

Keywords: Diabetic cardiomyopathy; H3K4me3; Mitochondrial function; PRDM16; Type 2 diabetes mellitus

DOI: https://doi.org/10.1016/j.metabol.2023.155658

Life Sci. 2023 Jul 10. pii: S0024-3205(23)00564-7. [Epub ahead of print]328 121929

Vericiguat preserved cardiac function and mitochondrial quality in a rat model of mitral regurgitation.

Peeraya Jungtanasomboon, Surunchana Nussaro, Hathaichanok Winwan, Patcharapol Suebthawinkul, Pakit Boonpala, Van Nhut Khanh Dong, Nakkawee Saengklub, Sarawut Kumphune, Yaowalak Panyasing, Anusak Kijtawornrat.

AIMS: New drugs for heart failure (HF) that target restoring the impaired NO-sGC-cGMP pathway are being developed. We aimed to investigate the effects of vericiguat, an sGC stimulator, on cardiac function, blood pressure (BP), cardiac mitochondrial quality, and cardiac fibrosis in rat models of chronic mitral regurgitation (MR).MATERIALS AND METHODS: We surgically induced MR in 20 Sprague-Dawley rats and performed sham procedures on 10 rats (negative control). Four weeks post-surgery, we randomly divided the MR rats into two groups: MR group and MR + vericiguat group. Vericiguat (0.5 mg/kg, PO) was administered once a day via oral gavage for 8 weeks, while the sham and MR groups received equivalent volumes of drinking water instead. We took echocardiography and BP measurements at baseline (4 weeks post-surgery) and at the end of study (8 weeks after treatment). At the study end, all rats were euthanized and their hearts were immediately collected, weighed, and used for histopathology and mitochondrial quality assessments.
KEY FINDINGS: Vericiguat preserved cardiac functions and structural remodeling in the MR rats, with significantly lower systolic BPs than baseline values (P < 0.05). Additionally, vericiguat significantly improved the mitochondrial quality by attenuating ROS production, depolarization and swelling when comparing the values in both groups (P < 0.05). The fibrosis area also significantly decreased in the MR + vericiguat group (P < 0.05).
SIGNIFICANCE: Vericiguat demonstrated cardioprotective effects on cardiac function, BP, and fibrosis by preserving mitochondrial quality in rats with HF due to MR.

Keywords: Cardiac function; Mitochondrial quality; Mitral regurgitation; Nitric oxide; Vericiguat; sGC stimulator

DOI: https://doi.org/10.1016/j.lfs.2023.121929