Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages

Zhao, Shuai; Zhou, Lei; Wang, Qin; Cao, Jia-Hao; Chen, Yan; Wang, Wei; Zhu, Bo-Da; Wei, Zhihong; Li, Rong; Li, Cong-Ye; Zhou, Gengyao; Tan, Zhen; Zhou, Heping; Li, Chengxiang; Gao, Haokao; Qin, Xu-Jun; Lian, Kun

doi:10.1016/j.redox.2023.102696

Cited by 11 publications

(6 citation statements)

References 51 publications

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“…Experimental study BCAA levels associated with AS pathogenesis [151] Cohort BCAA levels associated with coronary and carotid atherosclerosis [160] Experimental study (902 patients)…”

Section: Study Design Resultsmentioning

confidence: 99%

Section: Branched-chain Amino Acid In Cardiovascular Diseasementioning

confidence: 99%

“…Zhao et al discovered that increased BCAA levels lead to proinflammatory macrophage activation and AS progression [ 151 ]. Mitochondrial H2O2 (mtH2O2) levels observed in activated macrophages induced the formation of high-mobility group box 1 protein (HMGB1) and the activation of the Toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain-enhancer of activate B cells (NF-κB) pathway, which is modulated by BCAA catabolism [ 151 ]. Notably, recent research by Zhenyukh et al has suggested that elevated levels of BCAAs stimulate the PI3K-Akt/mTORC1 signaling pathway, triggering the formation of reactive oxygen species (ROS) and proinflammatory proteins [ 38 , 152 , 153 ].…”

Section: Branched-chain Amino Acid In Cardiovascular Diseasementioning

confidence: 99%

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Duality of Branched-Chain Amino Acids in Chronic Cardiovascular Disease: Potential Biomarkers versus Active Pathophysiological Promoters

Tanase,

Valasciuc,

Costea

et al. 2024

Nutrients

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Branched-chain amino acids (BCAAs), comprising leucine (Leu), isoleucine (Ile), and valine (Val), are essential nutrients vital for protein synthesis and metabolic regulation via specialized signaling networks. Their association with cardiovascular diseases (CVDs) has become a focal point of scientific debate, with emerging evidence suggesting both beneficial and detrimental roles. This review aims to dissect the multifaceted relationship between BCAAs and cardiovascular health, exploring the molecular mechanisms and clinical implications. Elevated BCAA levels have also been linked to insulin resistance (IR), type 2 diabetes mellitus (T2DM), inflammation, and dyslipidemia, which are well-established risk factors for CVD. Central to these processes are key pathways such as mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-light-chain-enhancer of activate B cells (NF-κB)-mediated inflammation, and oxidative stress. Additionally, the interplay between BCAA metabolism and gut microbiota, particularly the production of metabolites like trimethylamine-N-oxide (TMAO), adds another layer of complexity. Contrarily, some studies propose that BCAAs may have cardioprotective effects under certain conditions, contributing to muscle maintenance and metabolic health. This review critically evaluates the evidence, addressing the biological basis and signal transduction mechanism, and also discusses the potential for BCAAs to act as biomarkers versus active mediators of cardiovascular pathology. By presenting a balanced analysis, this review seeks to clarify the contentious roles of BCAAs in CVD, providing a foundation for future research and therapeutic strategies required because of the rising prevalence, incidence, and total burden of CVDs.

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“…Experimental study BCAA levels associated with AS pathogenesis [151] Cohort BCAA levels associated with coronary and carotid atherosclerosis [160] Experimental study (902 patients)…”

Section: Study Design Resultsmentioning

confidence: 99%

Section: Branched-chain Amino Acid In Cardiovascular Diseasementioning

confidence: 99%

Section: Branched-chain Amino Acid In Cardiovascular Diseasementioning

confidence: 99%

See 1 more Smart Citation

Duality of Branched-Chain Amino Acids in Chronic Cardiovascular Disease: Potential Biomarkers versus Active Pathophysiological Promoters

Tanase,

Valasciuc,

Costea

et al. 2024

Nutrients

View full text Add to dashboard Cite

show abstract

“…This impairment is characterized by the disruption of the mitochondrial membrane potential and the opening of the mitochondrial permeability transition pore. The accumulation of branched-chain keto acids (BCKAs) from the degraded BCAA facilitates ROS generation ( Zhao et al, 2023 ) . The metabolites, ROS, and oxidative stress crosstalk with fibroblasts activate profibrotic cascades, alter the turnover of the ECM, and ultimately shift the balance toward fibrosis.…”

Section: Metabolic Regulation Of Cardiac Homeostasismentioning

confidence: 99%

Cardiac fibrogenesis: an immuno-metabolic perspective

Hoque,

Gbadegoye,

Hassan

et al. 2024

Front. Physiol.

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Cardiac fibrosis is a major and complex pathophysiological process that ultimately culminates in cardiac dysfunction and heart failure. This phenomenon includes not only the replacement of the damaged tissue by a fibrotic scar produced by activated fibroblasts/myofibroblasts but also a spatiotemporal alteration of the structural, biochemical, and biomechanical parameters in the ventricular wall, eliciting a reactive remodeling process. Though mechanical stress, post-infarct homeostatic imbalances, and neurohormonal activation are classically attributed to cardiac fibrosis, emerging evidence that supports the roles of immune system modulation, inflammation, and metabolic dysregulation in the initiation and progression of cardiac fibrogenesis has been reported. Adaptive changes, immune cell phenoconversions, and metabolic shifts in the cardiac nonmyocyte population provide initial protection, but persistent altered metabolic demand eventually contributes to adverse remodeling of the heart. Altered energy metabolism, mitochondrial dysfunction, various immune cells, immune mediators, and cross-talks between the immune cells and cardiomyocytes play crucial roles in orchestrating the transdifferentiation of fibroblasts and ensuing fibrotic remodeling of the heart. Manipulation of the metabolic plasticity, fibroblast–myofibroblast transition, and modulation of the immune response may hold promise for favorably modulating the fibrotic response following different cardiovascular pathological processes. Although the immunologic and metabolic perspectives of fibrosis in the heart are being reported in the literature, they lack a comprehensive sketch bridging these two arenas and illustrating the synchrony between them. This review aims to provide a comprehensive overview of the intricate relationship between different cardiac immune cells and metabolic pathways as well as summarizes the current understanding of the involvement of immune–metabolic pathways in cardiac fibrosis and attempts to identify some of the previously unaddressed questions that require further investigation. Moreover, the potential therapeutic strategies and emerging pharmacological interventions, including immune and metabolic modulators, that show promise in preventing or attenuating cardiac fibrosis and restoring cardiac function will be discussed.

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“…As an important cytokine in in ammation and immunity, HMGB1 has been proven to act as a core mediator in the pathogenesis of atherosclerosis (AS), with its release triggering signi cant in ammatory responses driven by endothelial cells and in ltrating immune cells [9] . In addition, HMGB1 can also mediate plaque formation by stimulating macrophage migration and is a key factor in the development and instability of atherosclerotic plaques [10] . However, it remains unclear whether HMGB1 can serve as a risk warning factor for MPN patients with concurrent AS.…”

Section: Introductionmentioning

confidence: 99%

HMGB1 as a Biomarker for Myeloproliferative Neoplasm Complicated with Atherosclerosis

Wu,

Han,

Zhang

et al. 2024

Preprint

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Objective The study analyzed the correlation between levels of HMGB1 in patient's serum and biochemical indices related to atherosclerosis, clarifying the diagnostic value of HMGB1 in myeloproliferative neoplasm (MPN) complicated with atherosclerosis (AS). Methods Bone marrow and serum of MPN patients were collected; qPCR was used to detect the level of HMGN1 mRNA in bone marrow mononuclear cells; ELISA was used to measure the level of HMGB1 in serum. Relevant biochemical indices of the patients were also collected, and the correlation between these indices and HMGB1 was analyzed. Results Compared with the control group, the levels of HMGB1 in both bone marrow mononuclear cells and serum of MPN patients were significantly higher; Pearson correlation analysis showed that the level of HMGB1 in serum was negatively correlated with HDL-C and ApoA1; ROC curve showed that the AUC of serum HMGB1 in predicting AS complication in MPN was 0.929 (P < 0.001), with a sensitivity of 100.00% and a specificity of 78.05%; Logistic regression analysis showed that the level of HMGB1 in serum has statistical significance with whether the MPN patient has AS (P < 0.05). Conclusion The raised levels of HMGB1 in the bone marrow and serum of MPN patients show correlation with biochemical indices related to AS, which may provide reference for predicting AS complication in MPN patients.

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Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages

Cited by 11 publications

References 51 publications

Duality of Branched-Chain Amino Acids in Chronic Cardiovascular Disease: Potential Biomarkers versus Active Pathophysiological Promoters

Duality of Branched-Chain Amino Acids in Chronic Cardiovascular Disease: Potential Biomarkers versus Active Pathophysiological Promoters

Cardiac fibrogenesis: an immuno-metabolic perspective

HMGB1 as a Biomarker for Myeloproliferative Neoplasm Complicated with Atherosclerosis

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