| 1. |
- Alajbegovic, Azra, et al.
(författare)
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Molecular regulation of arterial aneurysms : Role of actin dynamics and microRNAs in vascular smooth muscle
- 2017
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 8:AUG, s. 569-569
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Tidskriftsartikel (refereegranskat)abstract
- Aortic aneurysms are defined as an irreversible increase in arterial diameter by morethan 50% relative to the normal vessel diameter. The incidence of aneurysm rupture isabout 10 in 100,000 persons per year and ruptured arterial aneurysms inevitably resultsin serious complications, which are fatal in about 40% of cases. There is also a hereditarycomponent of the disease and dilation of the ascending thoracic aorta is often associatedwith congenital heart disease such as bicuspid aortic valves (BAV). Furthermore, specificmutations that have been linked to aneurysm affect polymerization of actin filaments.Polymerization of actin is important to maintain a contractile phenotype of smooth musclecells enabling these cells to resist mechanical stress on the vascular wall caused by theblood pressure according to the law of Laplace. Interestingly, polymerization of actin alsopromotes smooth muscle specific gene expression via the transcriptional co-activatorMRTF, which is translocated to the nucleus when released from monomeric actin. Inaddition to genes encoding for proteins involved in the contractile machinery, recentstudies have revealed that several non-coding microRNAs (miRNAs) are regulated bythis mechanism. The importance of these miRNAs for aneurysm development is onlybeginning to be understood. This review will summarize our current understanding aboutthe influence of smooth muscle miRNAs and actin polymerization for the developmentof arterial aneurysms.
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| 2. |
- Alajbegovic, Azra, et al.
(författare)
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MRTFA overexpression promotes conversion of human coronary artery smooth muscle cells into lipid-laden foam cells
- 2021
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Ingår i: Vascular Pharmacology. - : Elsevier BV. - 1537-1891. ; 138
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Smooth muscle cells contribute significantly to lipid-laden foam cells in atherosclerotic plaques. However, the underlying mechanisms transforming smooth muscle cells into foam cells are poorly understood. The purpose of this study was to gain insight into the molecular mechanisms regulating smooth muscle foam cell formation. Approach and results: Using human coronary artery smooth muscle cells we found that the transcriptional co-activator MRTFA promotes lipid accumulation via several mechanisms, including direct transcriptional control of LDL receptor, enhanced fluid-phase pinocytosis and reduced lipid efflux. Inhibition of MRTF activity with CCG1423 and CCG203971 significantly reduced lipid accumulation. Furthermore, we demonstrate enhanced MRTFA expression in vascular remodeling of human vessels. Conclusions: This study demonstrates a novel role for MRTFA as an important regulator of lipid homeostasis in vascular smooth muscle cells. Thus, MRTFA could potentially be a new therapeutic target for inhibition of vascular lipid accumulation.
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| 3. |
- Alajbegovic, Azra, et al.
(författare)
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Regulation of microRNA expression in vascular smooth muscle by MRTF-A and actin polymerization
- 2017
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Ingår i: Biochimica et Biophysica Acta - Molecular Cell Research. - : Elsevier BV. - 0167-4889. ; 1864:6, s. 1088-1098
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Tidskriftsartikel (refereegranskat)abstract
- The dynamic properties of the actin cytoskeleton in smooth muscle cells play an important role in a number of cardiovascular disease states. The state of actin does not only mediate mechanical stability and contractile function but can also regulate gene expression via myocardin related transcription factors (MRTFs). These transcriptional co-activators regulate genes encoding contractile and cytoskeletal proteins in smooth muscle. Regulation of small non-coding microRNAs (miRNAs) by actin polymerization may mediate some of these effects. MiRNAs are short non-coding RNAs that modulate gene expression by post-transcriptional regulation of target messenger RNA.In this study we aimed to determine a profile of miRNAs that were 1) regulated by actin/MRTF-A, 2) associated with the contractile smooth muscle phenotype and 3) enriched in muscle cells. This analysis was performed using cardiovascular disease-focused miRNA arrays in both mouse and human cells. The potential clinical importance of actin polymerization in aortic aneurysm was evaluated using biopsies from mildly dilated human thoracic aorta in patients with stenotic tricuspid or bicuspid aortic valve.By integrating information from multiple qPCR based miRNA arrays we identified a group of five miRNAs (miR-1, miR-22, miR-143, miR-145 and miR-378a) that were sensitive to actin polymerization and MRTF-A overexpression in both mouse and human vascular smooth muscle. With the exception of miR-22, these miRNAs were also relatively enriched in striated and/or smooth muscle containing tissues. Actin polymerization was found to be dramatically reduced in the aorta from patients with mild aortic dilations. This was associated with a decrease in actin/MRTF-regulated miRNAs.In conclusion, the transcriptional co-activator MRTF-A and actin polymerization regulated a subset of miRNAs in vascular smooth muscle. Identification of novel miRNAs regulated by actin/MRTF-A may provide further insight into the mechanisms underlying vascular disease states, such as aortic aneurysm, as well as novel ideas regarding therapeutic strategies. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.
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| 4. |
- Alajbegovic, Azra
(författare)
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Transcriptional and post-transcriptional regulation of vascular smooth muscle cell phenotype - Implications for vascular disease states
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- As the world population is pushing toward 8 billion, cardiovascular diseases (CVD) remain the leading cause of death worldwide, representing 30% of all global deaths. A large body of work has recognized that smooth muscle cells (SMCs) surrounding the blood vessels play a prominent role in the development and progression of cardiovascular diseases. SMCs are highly specialized cells with the main function to maintain vascular tension and thereby regulate blood pressure and blood flow. SMCs retain remarkable plasticity. In response to changes in external cues, SMCs can modulate their phenotype from a highly mature contractile phenotype to a synthetic, proliferative phenotype. Although beneficial during key physiological processes such as wound healing, phenotypic modulation can contribute to the development and progression of several vascular disease states. Despite extensive studies on the transcriptional programs that define smooth muscle phenotype, the endogenous regulators that control smooth muscle specificity are still far from understood. The aim of this thesis was to gain further insight into the transcriptional and post-transcriptional regulation of gene expression that occurs during disease development and how these changes affect the function of the vascular wall.The work in the following papers has identified previously unknown mechanisms by which small non-coding RNAs (miRNAs), actin polymerization and transcriptional regulators MRTFA and GATA6 can contribute to the changes in vascular smooth muscle observed in vascular disease states. In summary, we show that actin polymerization and MRTFA regulate a profile of miRNAs that are downregulated in patients with mildly dilated aorta. Moreover, we demonstrate a novel role for MRTFA in lipid accumulation and foam cell formation. We further demonstrate the importance of miRNA-143 and miRNA-145 for vascular function and for adaptation to hypertension. Lastly, we show that GATA6 regulates migration of SMCs. A deeper understanding into the underlying molecular mechanisms is crucial in order to develop new efficient therapeutic approaches against cardiovascular disease states.
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| 5. |
- Albinsson, Sebastian, et al.
(författare)
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Patients with bicuspid and tricuspid aortic valve exhibit distinct regional microrna signatures in mildly dilated ascending aorta
- 2017
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Ingår i: Heart and Vessels. - : Springer Science and Business Media LLC. - 0910-8327 .- 1615-2573. ; 32:6, s. 750-767
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs are able to modulate gene expression in a range of diseases. We focused on microRNAs as potential contributors to the pathogenesis of ascending aorta (AA) dilatation in patients with stenotic tricuspid (TAV) or bicuspid aortic valve (BAV). Aortic specimens were collected from the ‘concavity’ and the ‘convexity’ of mildly dilated AAs and of normal AAs from heart transplant donors. Aortic RNA was analyzed through PCR arrays, profiling the expression of 84 microRNAs involved in cardiovascular disease. An in silico analysis identified the potential microRNA–mRNA interactions and the enriched KEGG pathways potentially affected by microRNA changes in dilated AAs. Distinct signatures of differentially expressed microRNAs are evident in TAV and BAV patients vs. donors, as well as differences between aortic concavity and convexity in patients only. MicroRNA changes suggest a switch of SMC phenotype, with particular reference to TAV concavity. MicroRNA changes potentially affecting mechanotransduction pathways exhibit a higher prevalence in BAV convexity and in TAV concavity, with particular reference to TGF-β1, Hippo, and PI3K/Akt/FoxO pathways. Actin cytoskeleton emerges as potentially affected by microRNA changes in BAV convexity only. MicroRNAs could play distinct roles in BAV and TAV aortopathy, with possible implications in diagnosis and therapy.
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| 6. |
- Daoud, Fatima, et al.
(författare)
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Inducible Deletion of YAP and TAZ in Adult Mouse Smooth Muscle Causes Rapid and Lethal Colonic Pseudo-Obstruction
- 2021
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Ingår i: Cellular and Molecular Gastroenterology and Hepatology. - : Elsevier BV. - 2352-345X. ; 11:2, s. 623-637
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Tidskriftsartikel (refereegranskat)abstract
- Background & AimsYAP (Yap1) and TAZ (Wwtr1) are transcriptional co-activators and downstream effectors of the Hippo pathway, which play crucial roles in organ size control and cancer pathogenesis. Genetic deletion of YAP/TAZ has shown their critical importance for embryonic development of the heart, vasculature, and gastrointestinal mesenchyme. The aim of this study was to determine the functional role of YAP/TAZ in adult smooth muscle cells in vivo.MethodsBecause YAP and TAZ are mutually redundant, we used YAP/TAZ double-floxed mice crossed with mice that express tamoxifen-inducible CreERT2 recombinase driven by the smooth muscle–specific myosin heavy chain promoter.ResultsDouble-knockout of YAP/TAZ in adult smooth muscle causes lethality within 2 weeks, mainly owing to colonic pseudo-obstruction, characterized by severe distension and fecal impaction. RNA sequencing in colon and urinary bladder showed that smooth muscle markers and muscarinic receptors were down-regulated in the YAP/TAZ knockout. The same transcripts also correlated with YAP/TAZ in the human colon. Myograph experiments showed reduced contractility to depolarization by potassium chloride and a nearly abolished muscarinic contraction and spontaneous activity in colon rings of YAP/TAZ knockout.ConclusionsYAP and TAZ in smooth muscle are guardians of colonic contractility and control expression of contractile proteins and muscarinic receptors. The knockout model has features of human chronic intestinal pseudo-obstruction and may be useful for studying this disease.
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| 7. |
- Daoud, Fatima, et al.
(författare)
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YAP and TAZ in Vascular Smooth Muscle Confer Protection Against Hypertensive Vasculopathy
- 2022
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Ingår i: Arteriosclerosis, Thrombosis, and Vascular Biology. - 1079-5642. ; 42:4, s. 428-443
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Tidskriftsartikel (refereegranskat)abstract
- Background: Hypertension remains a major risk factor for cardiovascular diseases, but the underlying mechanisms are not well understood. We hypothesize that appropriate mechanotransduction and contractile function in vascular smooth muscle cells are crucial to maintain vascular wall integrity. The Hippo pathway effectors YAP (yes-associated protein 1) and TAZ (WW domain containing transcription regulator 1) have been identified as mechanosensitive transcriptional coactivators. However, their role in vascular smooth muscle cell mechanotransduction has not been investigated in vivo. Methods: We performed physiological and molecular analyses utilizing an inducible smooth muscle-specific YAP/TAZ knockout mouse model. Results: Arteries lacking YAP/TAZ have reduced agonist-mediated contraction, decreased myogenic response, and attenuated stretch-induced transcriptional regulation of smooth muscle markers. Moreover, in established hypertension, YAP/TAZ knockout results in severe vascular lesions in small mesenteric arteries characterized by neointimal hyperplasia, elastin degradation, and adventitial thickening. Conclusions: This study demonstrates a protective role of YAP/TAZ against hypertensive vasculopathy.
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| 8. |
- Grossi, Mario, et al.
(författare)
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Inhibition of polyamine uptake potentiates the anti-proliferative effect of polyamine synthesis inhibition and preserves the contractile phenotype of vascular smooth muscle cells.
- 2015
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Ingår i: Journal of Cellular Physiology. - : Wiley. - 1097-4652 .- 0021-9541.
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Tidskriftsartikel (refereegranskat)abstract
- Increased vascular smooth muscle cell (VSMC) proliferation is a factor in atherosclerosis and injury-induced arterial (re)stenosis. Inhibition of polyamine synthesis by α-difluoro-methylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, attenuates VSMC proliferation with high sensitivity and specificity. However, cells can escape polyamine synthesis blockade by importing polyamines from the environment. To address this issue, polyamine transport inhibitors (PTIs) have been developed. We investigated the effects of the novel trimer44NMe (PTI-1) alone and in combination with DFMO on VSMC polyamine uptake, proliferation and phenotype regulation. PTI-1 efficiently inhibited polyamine uptake in primary mouse aortic and human coronary VSMCs in the absence as well as in the presence of DFMO. Interestingly, culture with DFMO for 2 days substantially (>95%) reduced putrescine (Put) and spermidine (Spd) contents without any effect on proliferation. Culture with PTI-1 alone had no effect on either polyamine levels or proliferation rate, but the combination of both treatments reduced Put and Spd levels below the detection limit and inhibited proliferation. Treatment with DFMO for a longer time period (4 days) reduced Put and Spd below their detection limits and reduced proliferation, showing that only a small pool of polyamines is needed to sustain VSMC proliferation. Inhibited proliferation by polyamine depletion was associated with maintained expression of contractile smooth marker genes. In cultured intact mouse aorta, PTI-1 potentiated the DFMO-induced inhibition of cell proliferation. The combination of endogenous polyamine synthesis inhibition with uptake blockade is thus a viable approach for targeting unwanted vascular cell proliferation in vivo, including vascular restenosis. This article is protected by copyright. All rights reserved.
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| 9. |
- Holmberg, Johan K, et al.
(författare)
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Laminin α2 Chain-Deficiency is Associated with microRNA Deregulation in Skeletal Muscle and Plasma.
- 2014
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 6:Jul 3
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Tidskriftsartikel (refereegranskat)abstract
- microRNAs (miRNAs) are widespread regulators of gene expression, but little is known of their potential roles in congenital muscular dystrophy type 1A (MDC1A). MDC1A is a severe form of muscular dystrophy caused by mutations in the gene encoding laminin α2 chain. To gain insight into the pathophysiological roles of miRNAs associated with MDC1A pathology, laminin α2 chain-deficient mice were evaluated by quantitative PCR. We demonstrate that expression of muscle-specific miR-1, miR-133a, and miR-206 is deregulated in laminin α2 chain-deficient muscle. Furthermore, expression of miR-223 and miR-21, associated with immune cell infiltration and fibrosis, respectively, is altered. Finally, we show that plasma levels of muscle-specific miRNAs are markedly elevated in laminin α2 chain-deficient mice and partially normalized in response to proteasome inhibition therapy. Altogether, our data suggest important roles for miRNAs in MDC1A pathology and we propose plasma levels of muscle-specific miRNAs as promising biomarkers for the progression of MDC1A.
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| 10. |
- Swärd, Karl, et al.
(författare)
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Emerging roles of the myocardin family of proteins in lipid and glucose metabolism
- 2016
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Ingår i: Journal of Physiology. - 1469-7793. ; 594:17, s. 4741-4752
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Tidskriftsartikel (refereegranskat)abstract
- Members of the myocardin family bind to the transcription factor serum response factor (SRF) and act as coactivators controlling genes of relevance for myogenic differentiation and motile function. Binding of SRF to DNA is mediated by genetic elements called CArG boxes, found often but not exclusively in muscle and growth controlling genes. Studies aimed at defining the full spectrum of these CArG elements in the genome (i.e. the CArGome) have in recent years, unveiled unexpected roles of the myocardin family proteins in lipid and glucose homeostasis. This coactivator family includes the protein myocardin (MYOCD), the myocardin-related transcription factors A and B (MRTF-A/MKL1 and MRTF-B/MKL2) and MASTR (MAMSTR). Here we discuss growing evidence that SRF-driven transcription is controlled by extracellular glucose through activation of the Rho-kinase pathway and actin polymerization. We also describe data showing that adipogenesis is influenced by MLK activity through actions upstream of peroxisome proliferator-activated receptor γ with consequences for whole body fat mass and insulin sensitivity. The recently demonstrated involvement of myocardin coactivators in the biogenesis of caveolae, Ω-shaped membrane invaginations of importance for lipid and glucose metabolism, is finally discussed. These novel roles of myocardin proteins may open the way for new unexplored strategies to combat metabolic diseases such as diabetes, which, at the current incidence, is expected to reach 333 million people worldwide by 2025. This review highlights newly discovered roles of myocardin-related transcription factors in lipid and glucose metabolism as well as novel insights into their well-established role as mediators of stretch-dependent effects in smooth muscle. As co-factors for serum response factor (SRF), MKLs regulates transcription of genes involved in the contractile function of smooth muscle cells. In addition to mechanical stimuli, this regulation has now been found to be promoted by extracellular glucose levels in smooth muscle. Recent reports also suggest that MKLs can regulate a subset of genes involved in the formation of lipid-rich invaginations in the cell membrane called caveolae. Finally, a potential role of MKLs in non-muscle cells has been discovered as they negatively influence adipocyte differentiation. (Figure presented.).
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