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Publikacije (103)

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A. Alajbegović, Fatima Daoud, N. Ali, Katarzyna Kawka, J. Holmberg, Sebastian Albinsson

Vascular smooth muscle cell plasticity plays a pivotal role in the pathophysiology of vascular diseases. Despite compelling evidence demonstrating the importance of transcription factor GATA6 in vascular smooth muscle, the functional role of GATA6 remains poorly understood. The aim of this study was to elucidate the role of GATA6 on cell migration and to gain insight into GATA6-sensitive genes in smooth muscle. We found that overexpression of GATA6 promotes migration of human coronary artery smooth muscle cells in vitro, and that silencing of GATA6 in smooth muscle cells resulted in reduced cellular motility. Furthermore, a complete microarray screen of GATA6-sensitive gene transcription resulted in 739 upregulated and 248 downregulated genes. Pathways enrichment analysis showed involvement of transforming growth factor beta (TGF-β) signaling which was validated by measuring mRNA expression level of several members. Furthermore, master regulators prediction based on microarray data revealed several members of (mitogen activated protein kinase) MAPK pathway as a master regulators, reflecting involvement of MAPK pathway also. Our findings provide further insights into the functional role of GATA6 in vascular smooth muscle and suggest that targeting GATA6 may constitute as a new approach to inhibit vascular smooth muscle migration.

Fatima Daoud, Marycarmen Arévalo Martínez, J. Holmberg, A. Alajbegović, N. Ali, C. Rippe, K. Swärd, Sebastian Albinsson

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.

A. Alajbegović, J. Holmberg, Fatima Daoud, C. Rippe, Gabriella Kalliokoski, M. Ekman, Sébastien Daudi, S. Ragnarsson et al.

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. (Less)

A. Alajbegović, J. Holmberg, M. Ekman, Sebastian Albinsson

Accumulation of lipids in in the arterial wall is a key feature of atherosclerosis. In atherosclerotic plaque from human and mouse origin it has recently become appreciated that more than 50% of total foam cells are derived from vascular smooth muscle cells (VSMCs) suggesting a much larger role for VSMCs in foam cell formation then previously assumed. The molecular mechanism behind this process and clinical significance remains yet to be elucidated. Myocardin Related Transcription Factor –A (MRTFA) is a transcriptional co‐activator that has been demonstrated to play a key role in pathological vascular remodelling including progression of atherosclerotic lesions. Here we aim to investigate the functional role of MRTFA on cholesterol loading of VSMCs.

J. Holmberg, Anirban Bhattachariya, A. Alajbegović, C. Rippe, M. Ekman, Diana Dahan, T. T. Hien, T. Boettger et al.

Objective— Pressure-induced myogenic tone is involved in autoregulation of local blood flow and confers protection against excessive pressure levels in small arteries and capillaries. Myogenic tone is dependent on smooth muscle microRNAs (miRNAs), but the identity of these miRNAs is unclear. Furthermore, the consequences of altered myogenic tone for hypertension-induced damage to small arteries are not well understood. Approach and Results— The importance of smooth muscle–enriched microRNAs, miR-143/145, for myogenic tone was evaluated in miR-143/145 knockout mice. Furthermore, hypertension-induced vascular injury was evaluated in mesenteric arteries in vivo after angiotensin II infusion. Myogenic tone was abolished in miR-143/145 knockout mesenteric arteries, whereas contraction in response to calyculin A and potassium chloride was reduced by ≈30%. Furthermore, myogenic responsiveness was potentiated by angiotensin II in wild-type but not in knockout mice. Angiotensin II administration in vivo elevated systemic blood pressure in both genotypes. Hypertensive knockout mice developed severe vascular lesions characterized by vascular inflammation, adventitial fibrosis, and neointimal hyperplasia in small mesenteric arteries. This was associated with depolymerization of actin filaments and fragmentation of the elastic laminae at the sites of vascular lesions. Conclusions— This study demonstrates that miR-143/145 expression is essential for myogenic responsiveness. During hypertension, loss of myogenic tone results in potentially damaging levels of mechanical stress and detrimental effects on small arteries. The results presented herein provide novel insights into the pathogenesis of vascular disease and emphasize the importance of controlling mechanical factors to maintain structural integrity of the vascular wall.

M. Tirić-Čampara, M. Denišlič, E. Tupković, J. Djelilovic-Vranic, A. Alajbegović, E. Campara

A. Alajbegović, J. Holmberg, Sebastian Albinsson

Aortic aneurysms are defined as an irreversible increase in arterial diameter by more than 50% relative to the normal vessel diameter. The incidence of aneurysm rupture is about 10 in 100,000 persons per year and ruptured arterial aneurysms inevitably results in serious complications, which are fatal in about 40% of cases. There is also a hereditary component of the disease and dilation of the ascending thoracic aorta is often associated with congenital heart disease such as bicuspid aortic valves (BAV). Furthermore, specific mutations that have been linked to aneurysm affect polymerization of actin filaments. Polymerization of actin is important to maintain a contractile phenotype of smooth muscle cells enabling these cells to resist mechanical stress on the vascular wall caused by the blood pressure according to the law of Laplace. Interestingly, polymerization of actin also promotes smooth muscle specific gene expression via the transcriptional co-activator MRTF, which is translocated to the nucleus when released from monomeric actin. In addition to genes encoding for proteins involved in the contractile machinery, recent studies have revealed that several non-coding microRNAs (miRNAs) are regulated by this mechanism. The importance of these miRNAs for aneurysm development is only beginning to be understood. This review will summarize our current understanding about the influence of smooth muscle miRNAs and actin polymerization for the development of arterial aneurysms.

Sebastian Albinsson, A. Della Corte, A. Alajbegović, Katarzyna K. Krawczyk, C. Bancone, U. Galderisi, M. Cipollaro, M. de Feo et al.

K. Swärd, Karin G. Stenkula, C. Rippe, A. Alajbegović, Maria F. Gomez, Sebastian Albinsson

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.

M. Grossi, O. Phanstiel, C. Rippe, K. Swärd, A. Alajbegović, Sebastian Albinsson, A. Forte, L. Persson et al.

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. J. Cell. Physiol. 231: 1334–1342, 2016. © 2015 Wiley Periodicals, Inc.

M. Tirić-Čampara, E. Tupković, M. Denišlič, M. Biscevic, A. Skopljak, Lejla Zunic, J. Djelilovic-Vranic, A. Alajbegović

Introduction: In this article are demonstrated differences in the aspects of the metabolic syndrome (MSy) between genders, as well as the association of MSy and neuropathy. The aim: The aim of our study was that in patients with newly discovered metabolic syndrome of both sexes make comparison of fasting blood glucose levels and after oral glucose tolerance test, as well as neurophysiological parameters of n.medianus and n.ulnaris. Patients and methods: All participants were examined dermatologically. The analysis included the 36 male and 36 female respondents with a newly discovered MSy. Results: The average age of men was 52.75±7.5 (40-65) years and women 52.1±7.7 (38-67) years. The average value of fasting blood glucose in women was 5.86±0.87 (4.5-8) mmol/L, and non significantly higher in men (p=0.0969) as 6.19±0.8 (4.7-8) mmol/L. Average values of blood sugar 120 minutes after oral glucose tolerance test were not significantly different (p=0.7052), and was 5.41±1.63 (3.3-9.7) mmol/L in women and 5.27±1.52 (2.7-9.8) mmol/L in men. Median motor velocity were significantly higher in women for n.medianus on the left (p=0.0024), n.ulnaris on the left (p=0.0081) and n.ulnaris on the right side (p=0.0293), and the median motor terminal latency were significantly longer in n.ulnaris on the left (p=0.0349) and n.ulnaris on the right side (p=0.011). There was no significant difference in the sensory conductivity velocity in n.medianus and n.ulnaris between the groups, but the amplitude with the highest peak of the sensory response was significantly higher in n.medianus on the left (p=0.0269) and n.ulnaris on the left side (p=0.0009) in female patients. Conclusion: The results indicate that there are differences in neurophysiological parameters of the investigated nerves between the genders, and that tested nerve structures in the course of MSy are affected slightly more in men. There were no significant differences in skin changes between genders.

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