Broad-acting therapeutic effects of miR-29b-chitosan on hypertension and diabetic complications

Jensen, David M; Han, Peng; Mangala, Lingegowda S.; López-Berestein, Gabriel; Sood, Anil K.; Liu, Jing; Kriegel, Alison J.; Usa, Kristie; Widlansky, Michael E.; Liang, Mingyu

doi:10.1016/j.ymthe.2022.08.007

Cited by 12 publications

(5 citation statements)

References 53 publications

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“…In addition, miR-29b targets PGC1α and regulates mitochondrial biogenesis [110]. Systemic delivery of low-dose miR-29b in diabetic mice improved myocardial performance with attenuation of cardiac fibrosis and improvement of endothelial function by suppressing the extracellular matrix gene expression [112]. Our recent study revealed that RAPA protected post-MI diabetic rabbit hearts by inhibiting myocardial remodeling and inflammation [70].…”

Section: Discussionmentioning

confidence: 95%

Integrated Analysis of lncRNA–miRNA–mRNA Regulatory Network in Rapamycin-Induced Cardioprotection against Ischemia/Reperfusion Injury in Diabetic Rabbits

Samidurai,

Olex,

Ockaili

et al. 2023

Cells

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The inhibition of mammalian target of rapamycin (mTOR) with rapamycin (RAPA) provides protection against myocardial ischemia/reperfusion (I/R) injury in diabetes. Since interactions between transcripts, including long non-coding RNA (lncRNA), microRNA(miRNA) and mRNA, regulate the pathophysiology of disease, we performed unbiased miRarray profiling in the heart of diabetic rabbits following I/R injury with/without RAPA treatment to identify differentially expressed (DE) miRNAs and their predicted targets of lncRNAs/mRNAs. Results showed that among the total of 806 unique miRNAs targets, 194 miRNAs were DE after I/R in diabetic rabbits. Specifically, eight miRNAs, including miR-199a-5p, miR-154-5p, miR-543-3p, miR-379-3p, miR-379-5p, miR-299-5p, miR-140-3p, and miR-497-5p, were upregulated and 10 miRNAs, including miR-1-3p, miR-1b, miR-29b-3p, miR-29c-3p, miR-30e-3p, miR-133c, miR-196c-3p, miR-322-5p, miR-499-5p, and miR-672-5p, were significantly downregulated after I/R injury. Interestingly, RAPA treatment significantly reversed these changes in miRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated the participation of miRNAs in the regulation of several signaling pathways related to I/R injury, including MAPK signaling and apoptosis. Furthermore, in diabetic hearts, the expression of lncRNAs, HOTAIR, and GAS5 were induced after I/R injury, but RAPA suppressed these lncRNAs. In contrast, MALAT1 was significantly reduced following I/R injury, with the increased expression of miR-199a-5p and suppression of its target, the anti-apoptotic protein Bcl-2. RAPA recovered MALAT1 expression with its sponging effect on miR-199-5p and restoration of Bcl-2 expression. The identification of novel targets from the transcriptome analysis in RAPA-treated diabetic hearts could potentially lead to the development of new therapeutic strategies for diabetic patients with myocardial infarction.

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Section: Discussionmentioning

confidence: 95%

Integrated Analysis of lncRNA–miRNA–mRNA Regulatory Network in Rapamycin-Induced Cardioprotection against Ischemia/Reperfusion Injury in Diabetic Rabbits

Samidurai,

Olex,

Ockaili

et al. 2023

Cells

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“…The expression of CVRF-associated miRNAs [miR-29b ( 24 , 25 ), miR-181a ( 26 , 28 ), and miR-494 ( 29 , 31 )] were determined. As a result of a small-sample screening experiment, plasma miR-29b and miR-494 levels were significantly decreased in sarcopenia patients compared to those without sarcopenia.…”

Section: Resultsmentioning

confidence: 99%

“…As a new, more sensitive, and potentially new biomarker for disease diagnosis and treatment, circulating miRNAs (c-miRNAs) have been reported to have a signature for patients with sarcopenia ( 22 , 23 ). The level change of one of these CVRF-associated miR-29b ( 24 , 25 ), miR-181-5p ( 26 – 28 ), and miR-494 ( 29 – 31 ) has been predicted to be related to patients with sarcopenia more recently. Considering that sarcopenia and CVD are closely related to CVRF, we can reasonably assume that sarcopenia can be assessed by measuring CVRF-specific c-miRNAs which can reflect health status.…”

Section: Introductionmentioning

confidence: 99%

Circulating miR-29b decrease in response to sarcopenia in patients with cardiovascular risk factors in older Chinese

Zhang

et al. 2022

Front. Cardiovasc. Med.

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IntroductionSarcopenia is a clinical syndrome characterized by a progressive and extensive decline in skeletal muscle mass, muscle strength, and function. Sarcopenia and cardiovascular diseases (CVDs) can coexist, which further decreases the quality of life of patients, and increases the mortality rate. MicroRNAs (miRNAs) are unique posttranscriptional regulators of gene expression whose function in aging-related sarcopenia and CVDs has recently begun to unravel. The aim of the present study is to investigate the relationship between sarcopenia and cardiovascular risk factors (CVRF) in the Chinese elderly and describe the circulating miRNAs in sarcopenia patients with the intention of identifying novel diagnostic and therapeutic tools.MethodsThe well-established CVRF of diabetes, hypertension, and dyslipidemia were assessed. Multiple logistic regression analyses and linear regressions were used to evaluate the components of CVRF and the number of CVRF in elderly patients with sarcopenia. Moreover, we used real-time RT-PCR to measure the abundance of the CVRF-related miRNAs in the plasma of a cohort of 93 control and sarcopenia individuals, including miR-29b, miR-181a, and miR-494.ResultsWe found that CVRF was associated with a high prevalence of sarcopenia in elderly Chinese populations After adjusting for potential confounders. Furthermore, hypertension and dyslipidemia, but not diabetes, were found to be significantly associated with sarcopenia. A linear increase in the prevalence of sarcopenia was found to be associated with the number of CVRF components in the elderly population. We found that plasma miR-29b levels were significantly down-regulated in response to sarcopenia in the elderly with CVRF. In particular, there was a remarkable correlation between miR-29b and appendicular skeletal muscle mass (ASM)/height2. Collectively, knowledge of CVRF, particularly hypertension and dyslipidemia, may help predict the risk of sarcopenia in the elderly. Our data also show that circulating miR-29b can be considered as possible biomarkers for sarcopenia, which may also be used in the CVD assessment of these patients.DiscussionWe found that the prevalence of sarcopenia was significantly proportional to the number of CVRF components. In particular, hypertension and dyslipidemia were significantly associated with a higher risk of sarcopenia in the adjusted models. Moreover, our study has been proven that c-miRNAs may be considered as possible biomarkers for sarcopenia as a new diagnostic tool to monitor response to treatment. There is also a pressing need for further research on sarcopenia and CVRF to understand their relationship and mechanism. These can provide more evidence to develop potential interventions to improve clinical outcomes.

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“…Vasoreactivity analysis was performed as described. 26,30 Briefly, third order mesenteric artery from naïve male rats were used in the current study. Isolated artery segments were mounted between two glass cannulas in a culture myograph chamber (DMT, 204CM).…”

Section: Methodsmentioning

confidence: 99%

Physiological role and mechanisms of action for a long noncoding haplotype region

Xue,

Mishra,

Liu

et al. 2024

Preprint

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Most common sequence variants associated with human traits are in noncoding regions of the genome, form haplotypes with other noncoding variants, and exhibit small effect sizes in the general population. Determining the physiological roles and mechanisms of action for these noncoding variants, particularly large haplotypes containing multiple variants, is both critical and challenging. To address this challenge, we developed an approach that integrates physiological studies in genetically engineered and phenotypically permissive animal models, precise editing of large haplotypes in human induced pluripotent stem cells (hiPSCs), and targeted chromatin conformation analysis. We applied this approach to examine the blood pressure associated rs1173771 locus, which includes a haplotype containing 11 single nucleotide polymorphisms (SNPs) spanning 17.4 kbp. Deleting the orthologous noncoding region in the genome of the Dahl salt-sensitive rat attenuated the salt-induced increase in systolic blood pressure by nearly 10 mmHg. This attenuation of hypertension appeared to be mediated by upregulation of the adjacent gene Npr3 (natriuretic peptide receptor 3) in arteries, enhancing vasodilation. The blood pressure-elevating and -lowering haplotypes were precisely reconstituted in hiPSCs using an efficient, two-step genome editing technique. The blood pressure-elevating haplotype decreased NPR3 expression in endothelial cells and vascular smooth muscle cells derived from the edited, isogenic hiPSCs. The influence of the haplotype was partially recapitulated by the sentinel SNP rs1173771. Additionally, the blood pressure-elevating haplotype showed significantly greater chromatin interactions with the NPR3 promoter region. This study illustrates the feasibility of ascertaining the physiological roles and mechanisms of action for large noncoding haplotypes. Our efficient, integrated, and targeted approach can be applied to investigate other noncoding variants.

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Broad-acting therapeutic effects of miR-29b-chitosan on hypertension and diabetic complications

Cited by 12 publications

References 53 publications

Integrated Analysis of lncRNA–miRNA–mRNA Regulatory Network in Rapamycin-Induced Cardioprotection against Ischemia/Reperfusion Injury in Diabetic Rabbits

Integrated Analysis of lncRNA–miRNA–mRNA Regulatory Network in Rapamycin-Induced Cardioprotection against Ischemia/Reperfusion Injury in Diabetic Rabbits

Circulating miR-29b decrease in response to sarcopenia in patients with cardiovascular risk factors in older Chinese

Physiological role and mechanisms of action for a long noncoding haplotype region

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