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- Albinsson, Sebastian, et al.
(author)
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Targeting smooth muscle microRNAs for therapeutic benefit in vascular disease.
- 2013
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In: Pharmacological Research. - : Elsevier BV. - 1096-1186 .- 1043-6618. ; 75:April,22, s. 28-36
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Research review (peer-reviewed)abstract
- In view of the bioinformatic projection that a third of all protein coding genes and essentially all biological pathways are under control of microRNAs (miRNAs), it is not surprising that this class of small RNAs plays roles in vascular disease progression. MiRNAs have been shown to be involved in cholesterol turnover, thrombosis, glucose homeostasis and vascular function. Some miRNAs appear to be specific for certain cells, and the role that such cell-specific miRNAs play in vascular disease is only beginning to be appreciated. A notable example is the miR-143/145 cluster which is enriched in mature and highly differentiated smooth muscle cells (SMCs). Here we outline and discuss the recent literature on SMC-expressed miRNAs in major vascular diseases, including atherosclerosis, neointima formation, aortic aneurysm formation, and pulmonary arterial hypertension. Forced expression of miR-145 emerges as a promising strategy for reduction and stabilization of atherosclerotic plaques as well as for reducing neointimal hyperplasia. It is concluded that if obstacles in the form of delivery and untoward effects of antimirs and mimics can be overcome, the outlook for targeting of SMC-specific miRNAs for therapeutic benefit in vascular disease is bright.
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- Chen, Yihong, et al.
(author)
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Identification of an osteopontin-derived peptide that binds neuropilin-1 and activates vascular repair responses and angiogenesis
- 2024
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In: Pharmacological Research. - 1096-1186. ; 205
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Journal article (peer-reviewed)abstract
- The osteopontin-derived peptide FOL-005 stimulates hair growth. Using ligand-receptor glyco-capture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005 and the more stable analogue FOL-026. X-ray diffraction and microscale thermophoresis analysis revealed that FOL-026 shares binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of VEGFR-2, ERK1/2 and AKT, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosis in vitro. FOL-026 also promoted angiogenesis in vivo as assessed by subcutaneous Matrigel plug and hind limb ischemia models. NRP-1 knock-down or treatment of NRP-1 antagonist EG00229 blocked the stimulatory effects of FOL-026 on endothelial cells. Exposure of human coronary artery smooth muscle cells to FOL-026 stimulated cell growth, migration, inhibited apoptosis, and induced VEGF gene expression and VEGFR-2/AKT phosphorylation by an NRP-1-dependent mechanism. RNA sequencing showed that FOL-026 activated pathways involved in tissue repair. These findings identify NRP-1 as the receptor for FOL-026 and show that its biological effects mimic that of growth factors binding to the VEGF receptor family. They also suggest that FOL-026 may have therapeutical potential in conditions that require vascular repair and/or enhanced angiogenesis.
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- Dludla, Phiwayinkosi V., et al.
(author)
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Uncoupling proteins as a therapeutic target to protect the diabetic heart
- 2018
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In: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 137, s. 11-24
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Research review (peer-reviewed)abstract
- Myocardial remodeling and dysfunction caused by accelerated oxidative damage is a widely reported phenomenon within a diabetic state. Altered myocardial substrate preference appears to be the major cause of enhanced oxidative stress-mediated cell injury within a diabetic heart. During this process, exacerbated free fatty acid flux causes an abnormal increase in mitochondrial membrane potential leading to the overproduction of free radical species and subsequent cell damage. Uncoupling proteins (UCPs) are expressed within the myocardium and can protect against free radical damage by modulating mitochondrial respiration, leading to reduced production of reactive oxygen species. Moreover, transgenic animals lacking UCPs have been shown to be more susceptible to oxidative damage and display reduced cardiac function when compared to wild type animals. This suggests that tight regulation of UCPs is necessary for normal cardiac function and in the prevention of diabetes-induced oxidative damage. This review aims to enhance our understanding of the pathophysiological mechanisms relating to the role of UCPs in a diabetic heart, and further discuss known pharmacological compounds and hormones that can protect a diabetic heart through the modulation of UCPs.
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- El-Seedi, Hesham R., et al.
(author)
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Cardenolides : Insights from chemical structure and pharmacological utility
- 2019
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In: Pharmacological Research. - : Academic Press. - 1043-6618 .- 1096-1186. ; 141, s. 123-175
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Journal article (peer-reviewed)abstract
- Cardiac glycosides (CGs) are a class of naturally occurring steroid-like compounds, and members of this class have been in clinical use for more than 1500 years. They have been used in folk medicine as arrow poisons, abortifacients, heart tonics, emetics, and diuretics as well as in other applications. The major use of CGs today is based on their ability to inhibit the membrane-bound Na + /K + -ATPase enzyme, and they are regarded as an effective treatment for congestive heart failure (CHF), cardiac arrhythmia and atrial fibrillation. Furthermore, increasing evidence has indicated the potential cytotoxic effects of CGs against various types of cancer. In this review, we highlight some of the structural features of this class of natural products that are crucial for their efficacy, some methods of isolating these compounds from natural resources, and the structural elucidation tools that have been used. We also describe their physicochemical properties and several modern biotechnological approaches for preparing CGs that do not require plant sources.
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- Eussen, Simone R. B. M., et al.
(author)
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Simultaneous intake of oat bran and atorvastatin reduces their efficacy to lower lipid levels and atherosclerosis in LDLr-/- mice
- 2011
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In: Pharmacological Research. - : Elsevier BV. - 1096-1186 .- 1043-6618. ; 64:1, s. 36-43
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Journal article (peer-reviewed)abstract
- The present study aimed to investigate the effects of separate and simultaneous dietary intake of atorvastatin (ATO) and the soluble fiber oat bran on serum and hepatic lipid levels and the degree of atherosclerosis. Ninety female LDL-receptor-deficient (LDLr-/-) mice were fed a Western-type diet containing either low dose (0.0025%), high dose (0.01%) or no ATO, with or without oat bran (27%) (n = 15 per group) for 16 weeks. Both ATO and oat bran were effective in reducing serum total cholesterol levels (low ATO: -5.48, high ATO: -9.12, oat bran: -3.82 mmol/l, compared to control (no ATO/no oat bran), all p < 0.0001). When oat bran was added to a low dose ATO, the cholesterol-lowering effects of this combination were 50% smaller compared to the low dose ATO diet alone (between-group difference: 2.77 mmol/l, p = 0.002), whereas total cholesterol decreased to a similar extent in the groups fed a high dose ATO, with or without oat bran (between-group difference: 1.10 mmol/l, p = 0.21). Serum LDL- and HDL-cholesterol, triglycerides, hepatic lipid levels and atherosclerotic lesion development showed a similar pattern. In conclusion, the efficacy of oat bran and atorvastatin to lower lipid levels and atherosclerosis is reduced after simultaneous intake. We hypothesize that oat bran inhibits the intestinal absorption of atorvastatin, and consequently its cholesterol-lowering effects. The effects are likely dependent on the type of statin and dietary fiber, and on the relative timing of intake of the statin and the dietary fiber. Future studies should focus on these aspects to provide further insight into the exact mechanism of this food-drug interaction. (C) 2011 Elsevier Ltd. All rights reserved.
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| 10. |
- Fredin, Maria Fritsch, 1970, et al.
(author)
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The application and relevance of ex vivo culture systems for assessment of IBD treatment in murine models of colitis
- 2008
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In: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 58:3-4, s. 222-231
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Journal article (peer-reviewed)abstract
- The aim of this study was to investigate the relevance of mouse ex vivo cultures as a first screening model for new therapeutic agents of Inflammatory Bowel Disease (IBD). Two murine models (dextran sodium sulphate (DSS)-induced colitis and Gαi2-deficient mice) and two anti-inflammatory agents (methyl-prednisolone and the proteasome inhibitor MG132) were evaluated. The in vivo effects of methyl-prednisolone were assessed in both models. Ex vivo colonic tissue from both mouse models were cultured in the presence or absence of the drugs and TaqMan Low-Density arrays were used to assess the regulation of inflammatory genes before and after drug treatment. Colitis induced a similar inflammatory gene profile in both mouse models in in vivo studies and in ex vivo cultures. The differences encountered reflected the different phases of colitis in the models, e.g. innate cytokine/chemokine profile in the DSS model and T cell related markers in Gαi2-deficient mice. After steroid treatment, a similar pattern of genes was suppressed in the two mouse models. We confirmed the suppression of inflammatory gene expression for IL-1β, IL-6 and iNOS in ex vivo and in vivo colons from both mouse models by quantitative RT-PCR. Importantly, the inflammatory responses in the murine ex vivo culture system reflected the in vivo response in the inflamed colonic tissue as assessed by changes in inflammatory gene expression, suggesting that the murine culture system can be used for validation of future IBD therapies.
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