| 1. |
- Hansson, Björn, et al.
(author)
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Adipose cell size changes are associated with a drastic actin remodeling
- 2019
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Journal article (peer-reviewed)abstract
- Adipose tissue plays a major role in regulating whole-body insulin sensitivity and energy metabolism. To accommodate surplus energy, the tissue rapidly expands by increasing adipose cell size (hypertrophy) and cell number (hyperplasia). Previous studies have shown that enlarged, hypertrophic adipocytes are less responsive to insulin, and that adipocyte size could serve as a predictor for the development of type 2 diabetes. In the present study, we demonstrate that changes in adipocyte size correlate with a drastic remodeling of the actin cytoskeleton. Expansion of primary adipocytes following 2 weeks of high-fat diet (HFD)-feeding in C57BL6/J mice was associated with a drastic increase in filamentous (F)-actin as assessed by fluorescence microscopy, increased Rho-kinase activity, and changed expression of actin-regulating proteins, favoring actin polymerization. At the same time, increased cell size was associated with impaired insulin response, while the interaction between the cytoskeletal scaffolding protein IQGAP1 and insulin receptor substrate (IRS)-1 remained intact. Reversed feeding from HFD to chow restored cell size, insulin response, expression of actin-regulatory proteins and decreased the amount of F-actin filaments. Together, we report a drastic cytoskeletal remodeling during adipocyte expansion, a process which could contribute to deteriorating adipocyte function.
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| 2. |
- Alajbegovic, Azra, et al.
(author)
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Molecular regulation of arterial aneurysms : Role of actin dynamics and microRNAs in vascular smooth muscle
- 2017
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 8:AUG, s. 569-569
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Journal article (peer-reviewed)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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| 3. |
- Alajbegovic, Azra, et al.
(author)
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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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In: Vascular Pharmacology. - : Elsevier BV. - 1537-1891. ; 138
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Journal article (peer-reviewed)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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| 4. |
- Alajbegovic, Azra, et al.
(author)
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Regulation of microRNA expression in vascular smooth muscle by MRTF-A and actin polymerization
- 2017
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In: Biochimica et Biophysica Acta - Molecular Cell Research. - : Elsevier BV. - 0167-4889. ; 1864:6, s. 1088-1098
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Journal article (peer-reviewed)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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| 5. |
- Albinsson, Sebastian, et al.
(author)
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Arterial remodeling and plasma volume expansion in caveolin-1 deficient mice.
- 2007
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In: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 293, s. 1222-1231
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Journal article (peer-reviewed)abstract
- Caveolin- 1 ( Cav- 1) is essential for the morphology of membrane caveolae and exerts a negative influence on a number of signaling systems, including nitric oxide ( NO) production and activity of the MAP kinase cascade. In the vascular system, ablation of caveolin- 1 may thus be expected to cause arterial dilatation and increased vessel wall mass ( remodeling). This was tested in Cav- 1 knockout ( KO) mice by a detailed morphometric and functional analysis of mesenteric resistance arteries, shown to lack caveolae. Quantitative morphometry revealed increased media thickness and media- to- lumen ratio in KO. Pressure- induced myogenic tone and flow- induced dilatation were decreased in KO arteries, but both were increased toward wild- type ( WT) levels following NO synthase ( NOS) inhibition. Isometric force recordings following NOS inhibition showed rightward shifts of passive and active length- force relationships in KO, and the force response to alpha 1- adrenergic stimulation was increased. In contrast, media thickness and force response of the aorta were unaltered in KO vs. WT, whereas lumen diameter was increased. Mean arterial blood pressure during isoflurane anesthesia was not different in KO vs. WT, but greater fluctuation in blood pressure over time was noted. Following NOS inhibition, fluctuations disappeared and pressure increased twice as much in KO ( 38 +/- 6%) compared with WT ( 17 +/- 3%). Tracer- dilution experiments showed increased plasma volume in KO. We conclude that NO affects blood pressure more in Cav- 1 KO than in WT mice and that restructuring of resistance vessels and an increased responsiveness to adrenergic stimulation compensate for a decreased tone in Cav- 1 KO mice.
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| 6. |
- Albinsson, Sebastian, et al.
(author)
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Can microRNAs control vascular smooth muscle phenotypic modulation and the response to injury?
- 2010
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In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; okt
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Journal article (peer-reviewed)abstract
- Vascular smooth muscle cell (VSMC) migration and proliferation are critical events in vascular proliferative diseases. Recent studies have established micro-RNAs (miRNAs) as important mediators for the modulation of VSMC phenotype by targeting transcription factors and the cytoskeleton, which act as molecular switches for VSMC differentiation. The importance of miRNAs for VSMC development, differentiation and function is evident by the fact that loss of the miRNA processing enzyme Dicer in VSMCs results in embryonic lethality due to severe vascular abnormalities. In addition, a role of specific miRNAs for neointimal hyperplasia following vascular injury has been reported which provides interesting possibilities for future therapeutical targets against vascular disease. Herein, we summarize recent advances regarding the role of miRNAs in VSMC phenotype modulation and response to injury.
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| 7. |
- Albinsson, Sebastian, et al.
(author)
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Differential dependence of stretch and shear stress signaling on caveolin-1 in the vascular wall
- 2008
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In: American Journal of Physiology: Cell Physiology. - : American Physiological Society. - 1522-1563 .- 0363-6143. ; 294, s. 271-279
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Journal article (peer-reviewed)abstract
- The role of caveolae in stretch- vs. flow-induced vascular responses was investigated using caveolin-1 deficient (KO) mice. Portal veins were stretched longitudinally for 5 min (acute) or 72 h (organ culture). Basal ERK1/2 and Akt phosphorylation were increased in organ-cultured KO veins, as were protein synthesis and vessel wall cross-section. Stretch stimulated acute phosphorylation of ERK1/2 and long-term phosphorylation of focal adhesion kinase (FAK) and cofilin, but did not affect Akt phosphorylation. Protein synthesis, and particularly synthesis of smooth muscle differentiation markers, was increased by stretch. These effects did not differ in portal veins from KO and control mice, which also showed the same contractile response to membrane depolarization and inhibition by the Rho kinase inhibitor Y-27632. KO carotid arteries had increased wall cross-section and responded to pressurization (120 mmHg) for 1 h with increased ERK1/2 but not Akt phosphorylation, similar to control arteries. Shear stress by flow for 15 min, on the other hand, increased phosphorylation of Akt in carotids from control but not KO mice. In conclusion, caveolin-1 contributes to a low basal ERK1/2 and Akt activity and is required for Akt-dependent signals in response to shear stress (flow), but is not essential for trophic effects of stretch (pressure) in the vascular wall. Key words: Hypertrophy, vasoconstriction, vascular smooth muscle, endothelium, nitric oxide.
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| 8. |
- Albinsson, Sebastian, et al.
(author)
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INTEGRATION OF SIGNAL PATHWAYS FOR STRETCH-DEPENDENT GROWTH AND DIFFERENTIATION IN VASCULAR SMOOTH MUSCLE.
- 2007
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In: American Journal of Physiology: Cell Physiology. - : American Physiological Society. - 1522-1563 .- 0363-6143. ; 293:May 16, s. 772-782
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Journal article (peer-reviewed)abstract
- Vascular smooth muscle phenotype is regulated by environmental factors, such as mechanical forces, which exert effects on signaling to differentiation and growth. We used the mouse portal vein in organ culture to investigate stretch-dependent activation of Akt, extracellular regulated protein kinase (ERK) and focal adhesion kinase (FAK), which have been suggested to be involved in the regulation of stretch-dependent protein synthesis. The role of actin polymerization in these signaling events was examined using the actin stabilizing agent jasplakinolide. Stretch caused a biphasic activation of FAK at 5-15 minutes and 24-72 hours, which may reflect first a direct phosphorylation of preexisting focal adhesions followed by a rearrangement of focal adhesions to accommodate for the increased mechanical load. Phosphorylation of ERK was increased by acute stretch but then decreased, and Akt did not have a distinct peak in stretch-induced phosphorylation. Inhibition of ERK, phosphatidylinositol 3-kinase (PI3K) or mammalian target of rapamycin (mTOR) reduced global but not contractile protein synthesis with maintained stretch sensitivity. Stabilization of actin filaments with jasplakinolide, in unstretched portal veins, resulted in increased ERK phosphorylation and global protein synthesis as well as synthesis of contractile proteins. In contrast, stretch during culture with jasplakinolide did not affect FAK phosphorylation or contractility. Therefore, remodeling of smooth muscle cells to adapt to stretch requires a dynamic cytoskeleton. Key words: actin polymerization, MAP kinase, PI3 kinase, focal adhesion kinase, protein synthesis.
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| 9. |
- Albinsson, Sebastian
(author)
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Mechanosensing in the vascular wall - the role of cellular microdomains in vascular remodeling
- 2007
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Doctoral thesis (other academic/artistic)abstract
- The vascular wall has a remarkable capacity to adapt to mechanical forces exerted by the intraluminal blood pressure and flow. This includes rapid change in contractile tone as well as chronic alteration of vessel structure if the stimulus persists. Stretch of the intact blood vessel wall promotes growth and contractile differentiation. The molecular mechanisms involved are not well defined, but contractile differentiation has been suggested to be mediated by polymerization of the cytoskeletal protein actin. Part of the machinery that signals growth may be assembled in membrane invaginations termed caveolae, and a role for caveolae in mechanosensing has accordingly been proposed. The studies summarized in this thesis aimed to determine the role of these two cellular domains in mechanosensitive signaling in the intact vascular wall using rat or mouse portal veins as well as carotid and small mesenteric arteries. In the portal vein, we found that stretch promotes contractile differentiation via Rho activation and actin polymerization. An intact actin cytoskeleton is required for stretch-induced synthesis of smooth muscle specific marker proteins and for global protein synthesis. We also found that stabilizing actin filaments produced the same effects as stretch on protein synthesis. Stretch dependency of growth and differentiation was maintained in mice lacking caveolin-1 and vascular caveolae. In arteries from these mice, a reduced myogenic tone was observed, which was mainly caused by excessive nitric oxide (NO) production. Blood pressure was however maintained in vivo despite increased NO production. Maintenance of blood pressure in the setting of increased NO production could be due to increased alpha1-adrenergic contraction, hypertrophic remodeling and increased plasma volume. In summary, the data suggest that stretch stimulates polymerization of actin, which is necessary for expression of smooth muscle differentiation markers and growth of the intact vascular wall. On the other hand, stretch-induced growth and differentiation is not dependent on caveolin-1 or caveolae, which may however play a role for contractile responses to mechanical stimuli.
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| 10. |
- Albinsson, Sebastian, et al.
(author)
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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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In: Heart and Vessels. - : Springer Science and Business Media LLC. - 0910-8327 .- 1615-2573. ; 32:6, s. 750-767
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Journal article (peer-reviewed)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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