Dapagliflozin protects heart function against type-4 cardiorenal syndrome through activation of PKM2/PP1/FUNDC1-dependent mitophagy

Shen, Yang; Peng, Xiaojie; Ji, Haizhe; Gong, Wei; Zhu, Hang; Wang, Jin

doi:10.1016/j.ijbiomac.2023.126116

Cited by 6 publications

(1 citation statement)

References 52 publications

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“…T2D may enhance the proliferation of Oxalobacter formigenes by inducing chronic intestinal inflammation and altering metabolic pathways related to oxalic acid processing 41 , 42 . This condition is characterized by heightened parasympathetic activity and local ATP release into the intestinal tract 43 - 45 . The relatively unaffected colonization of Oxalobacter formigenes by other bacteria suggests a stable colonization characteristic of this genus 46 .…”

Section: Discussionmentioning

confidence: 99%

Altered Gut Microbiota as a Potential Risk Factor for Coronary Artery Disease in Diabetes: A Two-Sample Bi-Directional Mendelian Randomization Study

Zeng,

Qiu,

Chen

et al. 2024

Int. J. Med. Sci.

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The current body of research points to a notable correlation between an imbalance in gut microbiota and the development of type 2 diabetes mellitus (T2D) as well as its consequential ailment, coronary artery disease (CAD). The complexities underlying the association, especially in the context of diabetic coronary artery disease (DCAD), are not yet fully understood, and the causal links require further clarification. In this study, a bidirectional Mendelian randomization (MR) methodology was utilized to explore the causal relationships between gut microbiota, T2D, and CAD. By analyzing data from the DIAGRAM, GERA, UKB, FHS, and mibioGen cohorts and examining GWAS databases, we sought to uncover genetic variants linked to T2D, CAD, and variations in gut microbiota and metabolites, aiming to shed light on the potential mechanisms connecting gut microbiota with DCAD. Our investigation uncovered a marked causal link between the presence of Oxalobacter formigenes and an increased incidence of both T2D and CAD. Specifically, a ten-unit genetic predisposition towards T2D was found to be associated with a 6.1% higher probability of an increase in the Oxalobacteraceae family's presence (β = 0.061, 95% CI = 0.002-0.119). In a parallel finding, an augmented presence of Oxalobacter was related to an 8.2% heightened genetic likelihood of CAD (β = 0.082, 95% CI = 0.026-0.137). This evidence indicates a critical pathway by which T2D can potentially raise the risk of CAD via alterations in gut microbiota. Additionally, our analyses reveal a connection between CAD risk and Methanobacteria, thus providing fresh perspectives on the roles of TMAO and carnitine in the etiology of CAD. The data also suggest a direct causal relationship between increased levels of certain metabolites -proline, lysophosphatidylcholine, asparagine, and salicylurate -and the prevalence of both T2D and CAD. Sensitivity assessments reinforce the notion that changes in Oxalobacter formigenes could pose a risk for DCAD. There is also evidence to suggest that DCAD may, in turn, affect the gut microbiota's makeup. Notably, a surge in serum TMAO levels in individuals with CAD, coinciding with a reduced presence of methanogens, has been identified as a potentially significant factor for future examination.

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Section: Discussionmentioning

confidence: 99%

Altered Gut Microbiota as a Potential Risk Factor for Coronary Artery Disease in Diabetes: A Two-Sample Bi-Directional Mendelian Randomization Study

Zeng,

Qiu,

Chen

et al. 2024

Int. J. Med. Sci.

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Phosphoglycerate mutase 5 exacerbates alcoholic cardiomyopathy in male mice by inducing prohibitin‐2 dephosphorylation and impairing mitochondrial quality control

Tao,

Qiu,

Zheng

et al. 2024

Clinical & Translational Med

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BackgroundThe induction of mitochondrial quality control (MQC) mechanisms is essential for the re‐establishment of mitochondrial homeostasis and cellular bioenergetics during periods of stress. Although MQC activation has cardioprotective effects in various cardiovascular diseases, its precise role and regulatory mechanisms in alcoholic cardiomyopathy (ACM) remain incompletely understood.MethodsWe explored whether two mitochondria‐related proteins, phosphoglycerate mutase 5 (Pgam5) and prohibitin 2 (Phb2), influence MQC in male mice during ACM.ResultsMyocardial Pgam5 expression was upregulated in a male mouse model of ACM. Notably, following ACM induction, heart dysfunction was markedly reversed in male cardiomyocyte‐specific Pgam5 knockout (Pgam5cKO) mice. Meanwhile, in alcohol‐treated male mouse‐derived neonatal cardiomyocytes, Pgam5 depletion preserved cell survival and restored mitochondrial dynamics, mitophagy, mitochondrial biogenesis and the mitochondrial unfolded protein response (mtUPR). We further found that in alcohol‐treated cardiomyocyte, Pgam5 binds Phb2 and induces its dephosphorylation at Ser91. Alternative transduction of phospho‐mimetic (Phb2S91D) and phospho‐defective (Phb2S9A) Phb2 mutants attenuated and enhanced, respectively, alcohol‐related mitochondrial dysfunction in cardiomyocytes. Moreover, transgenic male mice expressing Phb2S91D were resistant to alcohol‐induced heart dysfunction.ConclusionsWe conclude that ACM‐induced Pgam5 upregulation results in Pgam5‐dependent Phb2S91 dephosphorylation, leading to MQC destabilisation and mitochondrial dysfunction in heart. Therefore, modulating the Pgam5/Phb2 interaction could potentially offer a novel therapeutic strategy for ACM in male mice.Highlights Pgam5 knockout attenuates alcohol‐induced cardiac histopathology and heart dysfunction in male mice. Pgam5 KO reduces alcohol‐induced myocardial inflammation, lipid peroxidation and metabolic dysfunction in male mice. Pgam5 depletion protects mitochondrial function in alcohol‐exposed male mouse cardiomyocytes. Pgam5 depletion normalises MQC in ACM. EtOH impairs MQC through inducing Phb2 dephosphorylation at Ser91. Pgam5 interacts with Phb2 and induces Phb2 dephosphorylation. Transgenic mice expressing a Ser91 phospho‐mimetic Phb2 mutant are resistant to ACM.

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The role of glycolytic metabolic pathways in cardiovascular disease and potential therapeutic approaches

Chen,

Zou,

Song

et al. 2023

Basic Res Cardiol

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Cardiovascular disease (CVD) is a major threat to human health, accounting for 46% of non-communicable disease deaths. Glycolysis is a conserved and rigorous biological process that breaks down glucose into pyruvate, and its primary function is to provide the body with the energy and intermediate products needed for life activities. The non-glycolytic actions of enzymes associated with the glycolytic pathway have long been found to be associated with the development of CVD, typically exemplified by metabolic remodeling in heart failure, which is a condition in which the heart exhibits a rapid adaptive response to hypoxic and hypoxic conditions, occurring early in the course of heart failure. It is mainly characterized by a decrease in oxidative phosphorylation and a rise in the glycolytic pathway, and the rise in glycolysis is considered a hallmark of metabolic remodeling. In addition to this, the glycolytic metabolic pathway is the main source of energy for cardiomyocytes during ischemia–reperfusion. Not only that, the auxiliary pathways of glycolysis, such as the polyol pathway, hexosamine pathway, and pentose phosphate pathway, are also closely related to CVD. Therefore, targeting glycolysis is very attractive for therapeutic intervention in CVD. However, the relationship between glycolytic pathway and CVD is very complex, and some preclinical studies have confirmed that targeting glycolysis does have a certain degree of efficacy, but its specific role in the development of CVD has yet to be explored. This article aims to summarize the current knowledge regarding the glycolytic pathway and its key enzymes (including hexokinase (HK), phosphoglucose isomerase (PGI), phosphofructokinase-1 (PFK1), aldolase (Aldolase), phosphoglycerate metatase (PGAM), enolase (ENO) pyruvate kinase (PKM) lactate dehydrogenase (LDH)) for their role in cardiovascular diseases (e.g., heart failure, myocardial infarction, atherosclerosis) and possible emerging therapeutic targets.

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Dapagliflozin protects heart function against type-4 cardiorenal syndrome through activation of PKM2/PP1/FUNDC1-dependent mitophagy

Cited by 6 publications

References 52 publications

Altered Gut Microbiota as a Potential Risk Factor for Coronary Artery Disease in Diabetes: A Two-Sample Bi-Directional Mendelian Randomization Study

Altered Gut Microbiota as a Potential Risk Factor for Coronary Artery Disease in Diabetes: A Two-Sample Bi-Directional Mendelian Randomization Study

Phosphoglycerate mutase 5 exacerbates alcoholic cardiomyopathy in male mice by inducing prohibitin‐2 dephosphorylation and impairing mitochondrial quality control

The role of glycolytic metabolic pathways in cardiovascular disease and potential therapeutic approaches

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