Is miR-21 A Therapeutic Target in Cardiovascular Disease?
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PROVIDER: S-EPMC10552863 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:Oligonucleotide-based therapies are currently gaining attention as a new treatment option for relatively rare as well as common diseases such as cardiovascular disease. With the remarkable progression of new sequencing technologies, a further step towards personalized precision medicine to target a disease at a molecular level was taken. Such therapies may employ antisense oligonucleotides to modulate the expression of both protein coding and non-coding RNAs, such as microRNAs. The cardiorenal syndrome (CRS) is a complex and severe clinical condition where heart and renal dysfunction mutually affect one another. The underlying mechanisms remain largely unknown and current treatments of CRS are mainly supportive therapies which slow down the progression of the disease, but hardly improve the condition. The small non-coding RNA, microRNA-21 (miR-21), is dysregulated in various heart and kidney diseases and has been repeatedly suggested as therapeutic target for the treatment of CRS. Impressive preclinical results have been achieved by an antisense oligonucleotide-based therapy to effectively block the pro-fibrotic traits of miR-21. Since microRNA-mediated pathways are generally very well-conserved, there is considerable commercial interest with regards to clinical translation. In this review, we will summarize the role of miR-21 within the heart-kidney axis and discuss the advantages and pitfalls of miR-21 targeting therapeutic strategies in CRS.
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Project description:Diabetic nephropathy is the main cause of end-stage renal disease. MicroRNAs are powerful regulators of the genome, and global expression profiling revealed miR-21 to be among the most highly regulated microRNAs in kidneys of mice with diabetic nephropathy. In kidney biopsies of diabetic patients, miR-21 correlated with tubulointerstitial injury. In situ PCR analysis showed a specific enrichment of miR-21 in glomerular cells. We identified cell division cycle 25a (Cdc25a) and cyclin-dependent kinase 6 (Cdk6) as novel miR-21 targets in mesangial cells. miR-21-mediated repression of Cdc25a and Cdk6 resulted in impaired cell cycle progression and subsequent mesangial cell hypertrophy. miR-21 increased podocyte motility by regulating phosphatase and tensin homolog (Pten). miR-21 antagonism in vitro and in vivo in streptozotocin-induced diabetic mice decreased mesangial expansion, interstitial fibrosis, macrophage infiltration, podocyte loss, albuminuria, and fibrotic- and inflammatory gene expression. In conclusion, miR-21 antagonism rescued various functional and structural parameters in mice with diabetic nephropathy and, thus, might be a viable option in the treatment of patients with diabetic kidney disease.
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Project description:Liver disease, including hepatocellular carcinoma (HCC), is a major global health concern, claiming approximately 2 million lives worldwide annually, yet curative treatments remain elusive. In this study, we aimed to investigate the role of microRNA-21-5p (miR-21) in metabolic dysfunction-associated steatotic liver disease (previously NAFLD), metabolic-associated steatohepatitis (previously NASH), and HCC within the context of a Western high-fat diet, without additional choline (HFD) and offering potential therapeutic insights. We found that reduced miR-21 levels correlated with liver disease progression in WT mice fed on HFD, while miR-21 knockout mice showed exacerbated metabolic dysfunction, including obesity, hepatomegaly, hyperglycemia, insulin resistance, steatosis, fibrosis, and HCC. Our study reveals that miR-21 plays a protective role in metabolic syndrome and in the progression of liver disease to cancer. MiR-21 directly targets Transforming growth factor beta-induced (Tgfbi), a gene also known to be significantly upregulated and a potential oncogene in HCC. Further, our study showed that intervention with the administration of a miR-21 mimic in WT livers effectively improves insulin sensitivity, steatosis, fibrosis, Tgfbi expression and tumor burden in HFD conditions. These findings indicate that miR-21 could serve as an effective strategy to delay or prevent liver disease in high-fat-diet environments.
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Project description:Background and aimInterleukin-21 (IL-21) is primarily a T cell-derived cytokine; it is upregulated in patients with Crohn's Disease (CD) and could be a potential new therapeutic target in CD.MethodsIn human material, IL-21 and IL-21R expression was investigated by in situ hybridization (ISH) and immunohistochemistry (IHC) in noninflammatory bowel disease (non-IBD) controls and patients with CD. The pathologic role of IL-21 was examined in murine models of T cell-dependent and T cell-independent colitis, either with a neutralizing monoclonal antibody against IL-21 or with the transfer of CD4+CD45RBhighIL-21R-/- T cells. Colonic pathology was examined by endoscopy, histopathology, IHC, ELISA, and Luminex.ResultsIn the human intestine, IL-21 and IL-21R mRNA and protein-expressing cells were observed in the mucosa, in lymphoid aggregates of submucosa in non-IBD controls, and in lymphoid aggregates of muscularis externa in patients with CD. IL-21 expression was most abundant in germinal centers (GCs) of the lymphoid aggregates, and IL-21R expression assessed semiquantitatively, was significantly higher in patients with CD compared to non-IBD controls. Following prophylactic and interventive anti-IL-21 mAb treatment in the adoptive transfer (AdTr) model, clinical and pathological parameters were significantly reduced. The most persistent finding was a reduction in colonic infiltrating neutrophils. As well, Rag2-/- mice receiving CD4+CD45RBhighIL-21R-/- T cells developed less severe colitis compared to Rag2-/- mice receiving CD4+CD45RBhighIL-21R+/+ T cells. No effect of reduced IL-21 signalling was observed in T cell-independent colitis.ConclusionOur study shows that patients with CD have significant expression of IL-21 and IL-21R in the gut. As well, we show that neutralization of IL-21 in experimental T cell-driven colitis is associated with a reduction in clinical and pathological findings. This amelioration seems to be associated with a reduction in colon-infiltrating neutrophils.
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Project description:It is well recognized that the elevated plasma level of low-density lipoprotein-cholesterol (LDL-C) is a major risk factor for atherosclerosis and cardiovascular disease (CVD). Deposition of pro-atherogenic LDL-C, on the intima of arterial wall, contributes to plaque formation and atherosclerosis, which further leads to lowered blood flow to vital organs and increased risk of CVD. The most commonly used statin therapy is effective in reducing dyslipidemia and preventing cardiovascular events only in about half of the patient population. However, in patients with familial hypercholesterolemia, these drugs were not effective to meet the required goals of lower LDL-C, and to reduce the CVD risk. Furthermore, many patients even develop intolerability to statins and resistance. The identification of pro-protein convertase subtilisin/kexin type 9 (PCSK9) and the association of PCSK9 mutations with familial hypercholesterolemia led to the identification of PCSK9 as a new therapeutic target for lowering LDL-C and dyslipidemia-associated CVD. PCSK9 is found to promote the degradation of LDL-receptor (LDLR), thus rendering it unavailable for recycling to hepatocyte plasma membrane, leading to elevated levels of circulating LDL-C, as it cannot be taken up into cells. While gain-of-function mutations aggravate the degradation of LDLR as in familial hypercholesterolemia whereas loss of function mutations reduce the ability of PCSK9 to promote the degradation of LDLR and thus lower the plasma level of LDL-C and dyslipidemia. Monoclonal antibodies against PCSK9 are currently being tested in clinical trials and are found to be efficacious in countering the activity of PCSK9 and thus control the plasma LDL-C and triglycerides even in statin non-responsive patients and protect against dyslipidemia-related CVD.
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Project description:Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease without any approved treatment to-date despite intensive research efforts by researchers and pharmaceutical industry. Fibroblast growth factor (FGF)-21 has been gaining increasing attention as a possible contributing factor and thus therapeutic target for obesity-related metabolic disorders, including NAFLD, mainly due to its effects on lipid and carbohydrate metabolism. Most animal and human observational studies have shown higher FGF-21 concentrations in NAFLD than non-NAFLD, implying that FGF-21 may be increased to counteract hepatic steatosis and inflammation. However, although Mendelian Randomization studies have revealed that variations of FGF-21 levels within the physiological range may have effects in hyperlipidemia and possibly nonalcoholic steatohepatitis, they also indicate that FGF-21, in physiological concentrations, may fail to reverse NAFLD and may not be able to control obesity and other diseases, indicating a state of FGF-21 resistance or insensitivity that could not respond to administration of FGF-21 in supraphysiological concentrations. Interventional studies with FGF-21 analogs (eg, pegbelfermin, efruxifermin, BOS-580) in humans have provided some favorable results in Phase 1 and Phase 2 studies. However, the definite effect of FGF-21 on NAFLD may be clarified after the completion of the ongoing clinical trials with paired liver biopsies and histological endpoints. The aim of this review is to critically summarize experimental and clinical data of FGF-21 in NAFLD, in an attempt to highlight existing knowledge and areas of uncertainty, and subsequently, to focus on the potential therapeutic effects of FGF-21 and its analogs in NAFLD.
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Project description:Primary prevention of premature death is a public health concern worldwide. Circulating microRNAs (miRNAs) have been described as potential diagnostic biomarkers for diseases as cancer and cardiovascular disease (CVD). This case-cohort study aimed to investigate the potential relationship between circulating miRNAs and the risk of premature death. A total of 39,242 subjects provided baseline serum samples in 1988-1990. Of these, 345 subjects who died of intrinsic disease (< 65 years old) and for which measurable samples were available were included in this study. We randomly selected a sub-cohort of 879 subjects. Circulatring miR-21, miR-29a, and miR-126 were determined using qRT-PCR. Conditional logistic regression models were used to analyse the data with respect to stratified miRNA levels. Multivariable logistic regression revealed that subjects with high circulating miR-21 and miR-29a individual levels had a significantly higher risk of total death, cancer death, and CVD death than those with medium miR-21 and miR-29a individual levels. Conversely, subjects with low circulating miR-126 levels had a significantly higher risk of total death than those with medium levels. This suggests that circulating miRNAs are associated with the risk of premature death from cancer and CVD, identifying them as potential biomarkers for early detection of high-risk individuals.
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