bims-hafaim 2024-12-01 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2024–12–01
eight papers selected by
Kyle McCommis, Saint Louis University

SGLT2 inhibitors in the prevention of diabetic cardiomyopathy: Targeting the silent threat.
Inhibition of Cardiac p38 Highlights the Role of the Phosphoproteome in Heart Failure Progression.
The role of protein O-GlcNAcylation in diabetic cardiomyopathy.
Heart Failure: A Deficiency of Energy-A Path Yet to Discover and Walk.
PERM1 regulates mitochondrial energetics through O-GlcNAcylation in the heart.
Cardiovascular and renal effects of the combination therapy of a GLP-1 receptor agonist and an SGLT2 inhibitor in observational real-life studies.
Mitochondrial Reactive Oxygen Species Dysregulation in Heart Failure with Preserved Ejection Fraction: A Fraction of the Whole.
Lysophosphatidylethanolamine improves diastolic dysfunction by alleviating mitochondrial injury in the aging heart.

World J Cardiol. 2024 Nov 26. 16(11): 669-672

SGLT2 inhibitors in the prevention of diabetic cardiomyopathy: Targeting the silent threat.

Panayotis K Vlachakis, Panagiotis Theofilis, Dimitris Tousoulis.

  Heart failure (HF) is a major global health challenge, particularly among individuals with type 2 diabetes mellitus (T2DM), who are at significantly higher risk of developing HF. Diabetic cardiomyopathy, a unique form of heart disease, often progresses silently until advanced stages. Recent research has focused on sodium-dependent glucose transporter 2 inhibitors (SGLT2i), originally developed for hyperglycemia, which have shown potential in reducing cardiovascular risks, including HF hospitalizations, irrespective of diabetic status. In this editorial we comment on the article by Grubić Rotkvić et al published in the recent issue of the World Journal of Cardiology. The investigators examined the effects of SGLT2i on myocardial function in T2DM patients with asymptomatic HF, finding significant improvements in stroke volume index and reductions in systemic vascular resistance, suggesting enhanced cardiac output. Additionally, SGLT2i demonstrated anti-inflammatory and antioxidant effects, as well as blood pressure reduction, though the study's limitations-such as small sample size and observational design-necessitate larger randomized trials to confirm these findings. The study underscores the potential of early intervention with SGLT2i in preventing HF progression in T2DM patients.

Keywords:  Diabetes mellitus; Heart failure; Inflammation; Oxidative stress; Pathophysiology; Sodium-dependent glucose transporter 2 inhibitor

DOI:  https://doi.org/10.4330/wjc.v16.i11.669
bioRxiv. 2024 Nov 20. pii: 2024.11.20.624554. [Epub ahead of print]

Inhibition of Cardiac p38 Highlights the Role of the Phosphoproteome in Heart Failure Progression.

Sogol Sedighi, Ting Liu, Robert O'Meally, Robert N Cole, Brian O'Rourke, D Brian Foster.

Heart failure (HF) is a complex condition characterized by the inability of the heart to pump sufficient oxygen to the organs to meet their metabolic needs. Among the altered signal transduction pathways associated with HF pathogenesis, the p38 mitogen-activated protein kinase (p38 MAPK) pathway-activated in response to stress- has attracted considerable attention for its potential role in HF progression and cardiac hypertrophy. However, the exact mechanisms by which p38 MAPK influences HF remain unclear. Addressing knowledge gaps may provide insight on why p38 inhibition has yielded inconsistent outcomes in clinical trials. Here we investigate the effects of p38 MAPK inhibition via SB203580 on cardiac remodeling in a guinea pig model of HF and sudden cardiac death. Using a well-established HF model with ascending aortic constriction and daily isoproterenol (ACi) administration, we assessed proteomic changes across three groups: sham-operated controls, untreated ACi, and ACi treated with SB203580 (ACiSB). Cardiac function was evaluated by M-mode echocardiography, while proteome and phosphoproteome profiles were analyzed using multiplexed tandem mass tag labeling and LC-MS/MS. Our findings demonstrate that chronic SB203580 treatment offers protection against progressive decline in cardiac function in HF. The proteomic data indicate that SB203580-treatment exerts broad protection of the cardiac phosphoproteome, beyond inhibiting maladaptive p38-dependent phosphorylation, extending to PKA and AMPK networks among others, ultimately protecting the phosphorylation status of critical myofibrillar and Ca 2+ -handling proteins. Though SB203580 had a more restricted impact on widespread protein changes in HF, its biosignature was consistent with preserved mitochondrial energetics as well as reduced oxidative and inflammatory stress.

DOI: https://doi.org/10.1101/2024.11.20.624554
Biochem Soc Trans. 2024 Nov 27. pii: BST20240262. [Epub ahead of print]

The role of protein O-GlcNAcylation in diabetic cardiomyopathy.

John C Chatham, Adam R Wende.

  It is well established that diabetes markedly increases the risk of multiple types of heart disease including heart failure. However, despite substantial improvements in the treatment of heart failure in recent decades the relative increased risk associated with diabetes remains unchanged. There is increasing appreciation of the importance of the post translational modification by O-linked-N-acetylglucosamine (O-GlcNAc) of serine and threonine residues on proteins in regulating cardiomyocyte function and mediating stress responses. In response to diabetes there is a sustained increase in cardiac O-GlcNAc levels, which has been attributed to many of the adverse effects of diabetes on the heart. Here we provide an overview of potential mechanisms by which increased cardiac O-GlcNAcylation contributes to the adverse effects on the heart and highlight some of the key gaps in our knowledge.

Keywords:  O-GlcNAc; diabetes; glycosylation; myocardium

DOI:  https://doi.org/10.1042/BST20240262
Biomedicines. 2024 Nov 12. pii: 2589. [Epub ahead of print]12(11):

Heart Failure: A Deficiency of Energy-A Path Yet to Discover and Walk.

Ioannis Paraskevaidis, Christos Kourek, Dimitrios Farmakis, Elias Tsougos.

  Heart failure is a complex syndrome and our understanding and therapeutic approach relies mostly on its phenotypic presentation. Notably, the heart is characterized as the most energy-consuming organ, being both a producer and consumer, in order to satisfy multiple cardiac functions: ion exchange, electromechanical coordination, excitation-contraction coupling, etc. By obtaining further knowledge of the cardiac energy field, we can probably better characterize the basic pathophysiological events occurring in heart disease patients and understand the metabolic substance changes, the relationship between the alteration of energy production/consumption, and hence energetic deficiency not only in the heart as a whole but in every single cardiac territory, which will hopefully provide us with the opportunity to uncover the beginning of the heart failure process. In this respect, using (a) newer imaging techniques, (b) biomedicine, (c) nanotechnology, and (d) artificial intelligence, we can gain a deeper understanding of this complex syndrome. This, in turn, can lead to earlier and more effective therapeutic approaches, ultimately improving human health. To date, the scientific community has not given sufficient attention to the energetic starvation model. In our view, this review aims to encourage scientists and the medical community to conduct studies for a better understanding and treatment of this syndrome.

Keywords:  cardiac biochemical substrate; cardiac energy; cardiac metabolism; heart failure; mitochondria function; starving heart

DOI:  https://doi.org/10.3390/biomedicines12112589
J Mol Cell Cardiol. 2024 Nov 23. pii: S0022-2828(24)00189-5. [Epub ahead of print]198 1-12

PERM1 regulates mitochondrial energetics through O-GlcNAcylation in the heart.

Karthi Sreedevi, Amina James, Sara Do, Shreya Yedla, Sumaita Arowa, Shin-Ichi Oka, Adam R Wende, Alexey V Zaitsev, Junco S Warren.

  PERM1 was initially identified as a new downstream target of PGC-1α and ERRs that regulates mitochondrial bioenergetics in skeletal muscle. Subsequently, we and other groups demonstrated that PERM1 is also a positive regulator of mitochondrial bioenergetics in the heart. However, the exact mechanisms of regulatory functions of PERM1 remain poorly understood. O-GlcNAcylation is a post-translational modification of proteins that are regulated by two enzymes: O-GlcNAc transferase (OGT) that adds O-GlcNAc to proteins; O-GlcNAcase (OGA) that removes O-GlcNAc from proteins. O-GlcNAcylation is a powerful signaling mechanism mediating cellular responses to stressors and nutrient availability, which, among other targets, may influence cardiac metabolism. We hypothesized that PERM1 regulates mitochondrial energetics in cardiomyocytes through modulation of O-GlcNAcylation. We found that overexpression of PERM1 decreased the total levels of O-GlcNAcylated proteins, concomitant with decreased OGT and increased OGA expression levels. Luciferase gene reporter assay showed that PERM1 significantly decreases the promoter activity of Ogt without changing the promoter activity of Oga. The downregulation of OGT by PERM1 overexpression was mediated through its interaction with E2F1, a known transcription repressor of Ogt. A deliberate increase of O-GlcNAcylation through Oga silencing in cardiomyocytes decreased the basal and maximal mitochondrial respiration and ATP production rates, all of which were completely restored by PERM1 overexpression. Furthermore, excessive O-GlcNAcylation caused by the loss of PERM1 led to the increase of O-GlcNAcylated PGC-1α, a master regulator of mitochondrial bioenergetics, concurrent with the dissociation of PGC-1α from PPARα, a well-known transcription factor that regulates fatty acid β-oxidation. We conclude that PERM1 positively regulates mitochondrial energetics, in part, via suppressing O-GlcNAcylation in cardiac myocytes.

Keywords:  Cardiac metabolism; E2F1; Mitochondrial energetics; O-GlcNAcylation; PERM1; PGC-1α

DOI:  https://doi.org/10.1016/j.yjmcc.2024.11.002
Diabetes Metab. 2024 Nov 26. pii: S1262-3636(24)00086-7. [Epub ahead of print] 101594

Cardiovascular and renal effects of the combination therapy of a GLP-1 receptor agonist and an SGLT2 inhibitor in observational real-life studies.

André J Scheen.

   BACKGROUND: Combining a glucagon-like peptide-1 receptor agonist (GLP-1RA) and an sodium-glucose cotransporter 2 inhibitor (SGLT2i) improved cardiovascular (and renal) prognosis compared to either monotherapy in several post-hoc exploratory analyses of randomized controlled trials (RCTs) versus placebo carried out in patients with type 2 diabetes (T2DM) and high cardiovascular/renal risk. The aim of the present work is to verify if such a benefit of the combined therapy is also present in real-life clinical practice.
METHODS: An extended search of the literature was performed to select observational retrospective studies that compared cardiovascular and/or renal outcomes in patients with T2DM treated with a GLP-1RA/SGLT2i combination versus patients treated with either GLP-1RA monotherapy or SGLT2i monotherapy, in addition to standard of care therapy.
RESULTS: Nine observational studies showed that a GLP-1RA/SGLT2i combination is associated with a greater reduction in major adverse cardiovascular events (MACEs), hospitalization for heart failure and all-cause-mortality when compared to either GLP-1RA alone or SGLT2i alone, without obvious differences between the two monotherapies, including regarding heart failure. Results were obtained in different populations, including patients with atherosclerotic cardiovascular disease and/or heart failure. Only three observational studies gave information on renal outcomes, with a greater benefit when the GLP-1RA/SGLT2i combination was compared with GLP-1RA alone or SGLT2i alone.
CONCLUSION: In real-life conditions, the GLP-1RA/SGLT2i combination reduced cardiovascular and renal outcomes compared with both GLP-1RA monotherapy and SGLT2i monotherapy. Overall, observational studies confirm the results reported in post-hoc exploratory analyses of RCTs versus placebo.

Keywords:  Cardiovascular outcome; Combined therapy; GLP-1 receptor agonist; Renal outcome; SGLT2 inhibitor

DOI:  https://doi.org/10.1016/j.diabet.2024.101594
Antioxidants (Basel). 2024 Oct 31. pii: 1330. [Epub ahead of print]13(11):

Mitochondrial Reactive Oxygen Species Dysregulation in Heart Failure with Preserved Ejection Fraction: A Fraction of the Whole.

Caroline Silveira Martinez, Ancheng Zheng, Qingzhong Xiao.

  Heart failure with preserved ejection fraction (HFpEF) is a multifarious syndrome, accounting for over half of heart failure (HF) patients receiving clinical treatment. The prevalence of HFpEF is rapidly increasing in the coming decades as the global population ages. It is becoming clearer that HFpEF has a lot of different causes, which makes it challenging to find effective treatments. Currently, there are no proven treatments for people with deteriorating HF or HFpEF. Although the pathophysiologic foundations of HFpEF are complex, excessive reactive oxygen species (ROS) generation and increased oxidative stress caused by mitochondrial dysfunction seem to play a critical role in the pathogenesis of HFpEF. Emerging evidence from animal models and human myocardial tissues from failed hearts shows that mitochondrial aberrations cause a marked increase in mitochondrial ROS (mtROS) production and oxidative stress. Furthermore, studies have reported that common HF medications like beta blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists indirectly reduce the production of mtROS. Despite the harmful effects of ROS on cardiac remodeling, maintaining mitochondrial homeostasis and cardiac functions requires small amounts of ROS. In this review, we will provide an overview and discussion of the recent findings on mtROS production, its threshold for imbalance, and the subsequent dysfunction that leads to related cardiac and systemic phenotypes in the context of HFpEF. We will also focus on newly discovered cellular and molecular mechanisms underlying ROS dysregulation, current therapeutic options, and future perspectives for treating HFpEF by targeting mtROS and the associated signal molecules.

Keywords:  cardiac diastolic dysfunction; cardiovascular disease; heart failure; heart failure with preserved ejection fraction (HFpEF); mitochondrial; mitochondrial dysfunction; oxidative stress; reactive oxygen species; redox signal

DOI:  https://doi.org/10.3390/antiox13111330
J Lipid Res. 2024 Nov 21. pii: S0022-2275(24)00218-9. [Epub ahead of print] 100713

Lysophosphatidylethanolamine improves diastolic dysfunction by alleviating mitochondrial injury in the aging heart.

Guiwen Xu, Wei Xiao, Pengqi Sun, Yuanjun Sun, Xinyu Yang, Xiaomeng Yin, Yang Liu.

  Diastolic dysfunction in aging mice is linked to mitochondrial abnormalities, including mitochondrial morphology disorders and decreases in membrane potential. Studies also show that aberrant mitochondrial lipid metabolism impairs mitochondrial function in aging cardiomyocytes. Our lipidomic analysis revealed that phosphatidylethanolamine (PE) levels were significantly decreased in aging myocardial mitochondria. Here, we investigated whether reduction in PE levels in myocardial mitochondria contributes to mitochondrial injury as well as HFpEF pathogenesis, and whether modulation of PE levels could ameliorate aging-induced HFpEF. Echocardiography was used to assess cardiac diastolic function in adult and aging mice treated with lysophosphatidylethanolamine (LPE) or saline. Mitochondrial morphologies from tissue samples were evaluated by transmission electron microscopy (TEM), while mitochondrial membrane potential and reactive oxygen species (ROS) levels were assessed using JC-1, MitoSOX and DCFH-DA detection assays. We performed GO enrichment analysis between adult and aging mice and discovered significant enrichment in transcriptional programs associated with mitochondria and lipid metabolism. Also, mitochondrial PE levels were significantly decreased in aging cardiomyocytes. Treatment with LPE significantly enhanced PE content in aging mice and improved the structure of mitochondria in cardiac cells. Also, LPE treatment protected against aging-induced deterioration of mitochondrial injury, as evidenced by increased mitochondrial membrane potential and decreased mitochondrial ROS. Furthermore, treatment with LPE alleviated severe diastolic dysfunction in aging mice. Taken together, our results suggest that LPE treatment enhances PE levels in mitochondria and ameliorates aging-induced diastolic dysfunction in mice through a mechanism involving improved mitochondrial structure and function.

Keywords:  Aging; Diastolic dysfunction; Lipid; Lysophosphatidylethanolamine; Mitochondria

DOI:  https://doi.org/10.1016/j.jlr.2024.100713