Clinical Relevance of lncRNA and Mitochondrial Targeted Antioxidants as Therapeutic Options in Regulating Oxidative Stress and Mitochondrial Function in Vascular Complications of Diabetes

Pant, Tarun; Uche, Nnamdi; Juric, Matea; Bošnjak, Željko J.

doi:10.3390/antiox12040898

Cited by 16 publications

(9 citation statements)

References 176 publications

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“…MEG3 , is involved. In fact, the role of lncRNAs in endothelial dysfunction associated with metabolic derangements is not surprising due to their involvement in inflammation and oxidative stress (Li et al., 2022 ; Pant et al., 2023 ; Zhou et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Higher gestational weight gain delays wound healing and reduces expression of long non‐coding RNA KLRK1‐AS1 in neonatal endothelial progenitor cells

Weiss,

Schrüfer,

Tocantins

et al. 2023

The Journal of Physiology

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High gestational weight gain (GWG) is a cardiovascular risk factor and may disturb neonatal endothelial function. Long non‐coding RNAs (lncRNAs) regulate gene expression epigenetically and can modulate endothelial function. Endothelial colony forming cells (ECFCs), circulating endothelial precursors, are a recruitable source of endothelial cells and sustain endothelial function, vascular growth and repair. We here investigated whether higher GWG affects neonatal ECFC function and elucidated the role of lncRNAs herein. Wound healing of umbilical cord blood‐derived ECFCs after pregnancies with GWG <13 kg versus >13 kg was determined in a scratch assay and based on monolayer impedance after electric wounding (electric cell‐substrate impedance sensing, ECIS). LncRNA expression was analysed by RNA sequencing. The function of killer cell lectin‐like receptor K1 antisense RNA (KLRK1‐AS1) was investigated after siRNA‐based knockdown. Closure of the scratch was delayed by 25% (P = 0.041) in the higher GWG group and correlated inversely with GWG (R = −0.538, P = 0.012) in all subjects (n = 22). Similarly, recovery of the monolayer barrier after electric wounding was delayed (−11% after 20 h; P = 0.014; n = 15). Several lncRNAs correlated with maternal GWG, the most significant one being KLRK1‐AS1 (log2 fold change = −0.135, P < 0.001, n = 35). KLRK1‐AS1 knockdown (n = 4) reduced barrier recovery after electric wounding by 21% (P = 0.029) and KLRK1‐AS1 expression correlated with the time required for wound healing for both scratch (R = 0.447, P = 0.033) and impedance‐based assay (R = 0.629, P = 0.014). Higher GWG reduces wound healing of neonatal ECFCs, and lower levels of the lncRNA KLRK1‐AS1 may underlie this. imageKey points Maternal cardiovascular risk factors such as diabetes, obesity and smoking in pregnancy disturb fetal endothelial function, and we here investigated whether also high gestational weight gain (GWG) has an impact on fetal endothelial cells. Circulating endothelial progenitor cells (endothelial colony forming cells, ECFCs) are highly abundant in the neonatal blood stream and serve as a circulating pool for vascular growth and repair. We revealed that higher GWG delays wound healing capacity of ECFCs in vitro. We identified the regulatory RNA lncRNA KLRK1‐AS1 as a link between GWG and delayed ECFC wound healing. Our data show that high GWG, independent of pre‐pregnancy BMI, affects neonatal ECFC function.

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Section: Discussionmentioning

confidence: 99%

Higher gestational weight gain delays wound healing and reduces expression of long non‐coding RNA KLRK1‐AS1 in neonatal endothelial progenitor cells

Weiss,

Schrüfer,

Tocantins

et al. 2023

The Journal of Physiology

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“…The deficient activity of Complex I caused by m.G11696A mutation would increase the production of ROS [ 66 ]. Excess ROS can increase mitochondrial dysfunction, protein damage, lipid peroxidation, and impair antioxidant functions [ 67 ]. Thus promoting pancreatic β-cell death or apoptosis and contributing to T2DM progression [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Diabetes Is Associated with the ND4 G11696A Mutation

et al. 2023

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Type 2 diabetes mellitus (T2DM) is a common endocrine disorder which remains a large challenge for clinicians. Previous studies have suggested that mitochondrial dysfunction plays an active role in T2DM progression, but a detailed mechanism is still elusive. In the current study, two Han Chinese families with maternally inherited T2DM were evaluated using clinical, genetic, molecular, and biochemical analyses. The mitochondrial genomes were PCR amplified and sequenced. Phylogenetic and bioinformatic analyses were used to assess the potential pathogenicity of mitochondrial DNA (mtDNA) mutations. Interestingly, the matrilineal relatives of these pedigrees exhibited variable severity of T2DM, in particular, the age at onset of T2DM varied from 26 to 65 years, with an average of 49 years. Sequence analysis revealed the presence of ND4 G11696A mutation, which resulted in the substitution of an isoleucine for valine at amino acid (AA) position 312. Indeed, this mutation was present in homoplasmy only in the maternal lineage, not in other members of these families, as well as 200 controls. Furthermore, the m.C5601T in the tRNAAla and novel m.T5813C in the tRNACys, showing high evolutional conservation, may contribute to the phenotypic expression of ND4 G11696A mutation. In addition, biochemical analysis revealed that cells with ND4 G11696A mutation exhibited higher levels of reactive oxygen species (ROS) productions than the controls. In contrast, the levels of mitochondrial membrane potential (MMP), ATP, mtDNA copy number (mtDNA-CN), Complex I activity, and NAD+/NADH ratio significantly decreased in cell lines carrying the m.G11696A and tRNA mutations, suggesting that these mutations affected the respiratory chain function and led to mitochondrial dysfunction that was involved in T2DM. Thus, our study broadened the clinical phenotypes of m.G11696A mutation.

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“…The application of lncRNA vaccines presents a promising avenue for addressing specific pathological aspects of VCI. By leveraging the regulatory role of lncRNAs, these vaccines hold potential in modulating neuroinflammation [ 145 ], oxidative stress [ 146 ], and other processes related to VCI. LncRNAs have been found to hold potential value as vaccines in other diseases.…”

Section: Exploring the Intersection Of Lncrna And Immunization In Vcimentioning

confidence: 99%

Potential Intersections between lncRNA, Vascular Cognitive Impairment, and Immunization Strategies: Insights and Future Directions

Fan,

Xiao,

Zhang

2024

Vaccines

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Vascular cognitive impairment (VCI) encompasses a wide range of cognitive disorders stemming from cerebrovascular issues, such as strokes or small vessel disease. These conditions often pose challenges to traditional diagnostic approaches due to their multifactorial nature and varied clinical presentations. Recently, next-generation sequencing (NGS) technologies have provided detailed analyses of long non-coding RNAs (lncRNAs) in the molecular pathobiology of VCI. These new findings help with molecular-based diagnostics and treatments of VCI. Within this realm, the concept of immune modulation, especially through specific vaccinations, emerges as a promising therapeutic strategy in VCI mitigation. In this review, we comprehensively elucidate the function of lncRNAs in VCI, emphasizing the advanced understanding of VCI’s molecular underpinnings made possible through NGS technologies. Significant focus is placed on the immune system’s role in VCI, particularly the neuroinflammatory processes which are consequential to cerebrovascular abnormalities. We believe that lncRNAs participate in regulating these immunological pathways, potentially guiding the development of vaccines targeting VCI. In this context, we propose a novel perspective: using knowledge about lncRNA profiles and functions to guide vaccine development, we can potentially exploit the body’s immune response to mitigate or prevent VCI. This approach has the potential to revolutionize VCI management by introducing targeted immunization strategies informed by molecular signatures, a concept that remains largely unexplored in current research endeavors. In addition, we summarize current progress and propose future directions, advocating for robust, interdisciplinary studies to validate the potential intersections between lncRNA landscapes, VCI pathology, and immunology. This review aims to spur innovative research and promote the development of lncRNA-informed vaccine strategies as proactive interventions against the cognitive consequences of VCI.

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Clinical Relevance of lncRNA and Mitochondrial Targeted Antioxidants as Therapeutic Options in Regulating Oxidative Stress and Mitochondrial Function in Vascular Complications of Diabetes

Cited by 16 publications

References 176 publications

Higher gestational weight gain delays wound healing and reduces expression of long non‐coding RNA KLRK1‐AS1 in neonatal endothelial progenitor cells

Higher gestational weight gain delays wound healing and reduces expression of long non‐coding RNA KLRK1‐AS1 in neonatal endothelial progenitor cells

Mitochondrial Diabetes Is Associated with the ND4 G11696A Mutation

Potential Intersections between lncRNA, Vascular Cognitive Impairment, and Immunization Strategies: Insights and Future Directions

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