Phenotypic Modulation of Smooth Muscle Cells in Atherosclerosis Is Associated With Downregulation of LMOD1, SYNPO2, PDLIM7, PLN, and SYNM
OBJECTIVE—Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to pla...
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| Published in | Arteriosclerosis, thrombosis, and vascular biology Vol. 36; no. 9; pp. 1947 - 1961 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Heart Association, Inc
01.09.2016
American Heart Association |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1079-5642 1524-4636 1524-4636 |
| DOI | 10.1161/ATVBAHA.116.307893 |
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| Abstract | OBJECTIVE—Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability.
APPROACH AND RESULTS—Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7, and PLN expression positively correlated to typical SMC markers in plaques (Pearson r>0.6, P<0.0001) and in rat intimal hyperplasia (r>0.8, P<0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation-sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN, and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation.
CONCLUSIONS—We identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation. |
|---|---|
| AbstractList | OBJECTIVE—Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability.
APPROACH AND RESULTS—Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7, and PLN expression positively correlated to typical SMC markers in plaques (Pearson r>0.6, P<0.0001) and in rat intimal hyperplasia (r>0.8, P<0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation-sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN, and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation.
CONCLUSIONS—We identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation. Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability.OBJECTIVEKey augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability.Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7, and PLN expression positively correlated to typical SMC markers in plaques (Pearson r>0.6, P<0.0001) and in rat intimal hyperplasia (r>0.8, P<0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation-sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN, and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation.APPROACH AND RESULTSMuscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7, and PLN expression positively correlated to typical SMC markers in plaques (Pearson r>0.6, P<0.0001) and in rat intimal hyperplasia (r>0.8, P<0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation-sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN, and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation.We identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation.CONCLUSIONSWe identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation. Objective— Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability. Approach and Results— Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7 , and PLN expression positively correlated to typical SMC markers in plaques (Pearson r >0.6, P <0.0001) and in rat intimal hyperplasia ( r >0.8, P <0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation-sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN , and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation. Conclusions— We identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation. Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability. Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7, and PLN expression positively correlated to typical SMC markers in plaques (Pearson r>0.6, P<0.0001) and in rat intimal hyperplasia (r>0.8, P<0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation-sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN, and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation. We identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation. |
| Author | Lengquist, Mariette Tremoli, Elena Veglia, Fabrizio Magné, Joelle Quertermous, Thomas Miller, Clint L. Jin, Hong de Faire, Ulf Li, Yuhuang Eriksson, Per Kronqvist, Malin Hansson, Göran K. Paulsson-Berne, Gabrielle Baldassarre, Damiano Röhl, Samuel Perisic Matic, Ljubica Ehrenborg, Ewa Sabater-Lleal, Maria Lehtiö, Janne Ericsson, Ida Diez, Maria Gonzalez Vukojević, Vladana Vesterlund, Mattias Roy, Joy Rykaczewska, Urszula Aldi, Silvia Hedin, Ulf Hamsten, Anders Humphries, Steve E. Razuvaev, Anton Lindeman, Jan H.N. Paloschi, Valentina Odeberg, Jacob Maegdefessel, Lars |
| AuthorAffiliation | From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), and Department of Clinical Neuroscience, Center for Molecular Medicine (V.V.), Karolinska Institutet, Solna, Sweden; Division of Vascular Surgery, Stanford University, CA (C.L.M., T.Q.); Science for Life Laboratory, Solna, Sweden (M.V., J.L.); Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Italy (D.B., E.T.); Dipartimento di Scienze Cliniche e di Comunità, Centro Cardiologico Monzino, IRCCS, Milan, Italy (D.B., F.V., E.T.); British Heart Foundation Laboratories, Department of Medicine, University College of London, United Kingdom (S.E.H.); Department of Cardiology, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden (U.d.F.); Science f |
| AuthorAffiliation_xml | – name: From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), and Department of Clinical Neuroscience, Center for Molecular Medicine (V.V.), Karolinska Institutet, Solna, Sweden; Division of Vascular Surgery, Stanford University, CA (C.L.M., T.Q.); Science for Life Laboratory, Solna, Sweden (M.V., J.L.); Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Italy (D.B., E.T.); Dipartimento di Scienze Cliniche e di Comunità, Centro Cardiologico Monzino, IRCCS, Milan, Italy (D.B., F.V., E.T.); British Heart Foundation Laboratories, Department of Medicine, University College of London, United Kingdom (S.E.H.); Department of Cardiology, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden (U.d.F.); Science for Life Laboratory, Department of Proteomics, Stockholm, Sweden (J.O.); and Department of Vascular Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.) |
| Author_xml | – sequence: 1 givenname: Ljubica surname: Perisic Matic fullname: Perisic Matic, Ljubica organization: From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), and Department of Clinical Neuroscience, Center for Molecular Medicine (V.V.), Karolinska Institutet, Solna, Sweden; Division of Vascular Surgery, Stanford University, CA (C.L.M., T.Q.); Science for Life Laboratory, Solna, Sweden (M.V., J.L.); Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Italy (D.B., E.T.); Dipartimento di Scienze Cliniche e di Comunità, Centro Cardiologico Monzino, IRCCS, Milan, Italy (D.B., F.V., E.T.); British Heart Foundation Laboratories, Department of Medicine, University College of London, United Kingdom (S.E.H.); Department of Cardiology, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden (U.d.F.); Science for Life Laboratory, Department of Proteomics, Stockholm, Sweden (J.O.); and Department of Vascular Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.) – sequence: 2 givenname: Urszula surname: Rykaczewska fullname: Rykaczewska, Urszula – sequence: 3 givenname: Anton surname: Razuvaev fullname: Razuvaev, Anton – sequence: 4 givenname: Maria surname: Sabater-Lleal fullname: Sabater-Lleal, Maria – sequence: 5 givenname: Mariette surname: Lengquist fullname: Lengquist, Mariette – sequence: 6 givenname: Clint surname: Miller middlename: L. fullname: Miller, Clint L. – sequence: 7 givenname: Ida surname: Ericsson fullname: Ericsson, Ida – sequence: 8 givenname: Samuel surname: Röhl fullname: Röhl, Samuel – sequence: 9 givenname: Malin surname: Kronqvist fullname: Kronqvist, Malin – sequence: 10 givenname: Silvia surname: Aldi fullname: Aldi, Silvia – sequence: 11 givenname: Joelle surname: Magné fullname: Magné, Joelle – sequence: 12 givenname: Valentina surname: Paloschi fullname: Paloschi, Valentina – sequence: 13 givenname: Mattias surname: Vesterlund fullname: Vesterlund, Mattias – sequence: 14 givenname: Yuhuang surname: Li fullname: Li, Yuhuang – sequence: 15 givenname: Hong surname: Jin fullname: Jin, Hong – sequence: 16 givenname: Maria surname: Diez middlename: Gonzalez fullname: Diez, Maria Gonzalez – sequence: 17 givenname: Joy surname: Roy fullname: Roy, Joy – sequence: 18 givenname: Damiano surname: Baldassarre fullname: Baldassarre, Damiano – sequence: 19 givenname: Fabrizio surname: Veglia fullname: Veglia, Fabrizio – sequence: 20 givenname: Steve surname: Humphries middlename: E. fullname: Humphries, Steve E. – sequence: 21 givenname: Ulf surname: de Faire fullname: de Faire, Ulf – sequence: 22 givenname: Elena surname: Tremoli fullname: Tremoli, Elena – sequence: 23 givenname: Jacob surname: Odeberg fullname: Odeberg, Jacob – sequence: 24 givenname: Vladana surname: Vukojević fullname: Vukojević, Vladana – sequence: 25 givenname: Janne surname: Lehtiö fullname: Lehtiö, Janne – sequence: 26 givenname: Lars surname: Maegdefessel fullname: Maegdefessel, Lars – sequence: 27 givenname: Ewa surname: Ehrenborg fullname: Ehrenborg, Ewa – sequence: 28 givenname: Gabrielle surname: Paulsson-Berne fullname: Paulsson-Berne, Gabrielle – sequence: 29 givenname: Göran surname: Hansson middlename: K. fullname: Hansson, Göran K. – sequence: 30 givenname: Jan surname: Lindeman middlename: H.N. fullname: Lindeman, Jan H.N. – sequence: 31 givenname: Per surname: Eriksson fullname: Eriksson, Per – sequence: 32 givenname: Thomas surname: Quertermous fullname: Quertermous, Thomas – sequence: 33 givenname: Anders surname: Hamsten fullname: Hamsten, Anders – sequence: 34 givenname: Ulf surname: Hedin fullname: Hedin, Ulf |
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| ContentType | Journal Article |
| Copyright | 2016 American Heart Association, Inc. Distributed under a Creative Commons Attribution 4.0 International License |
| Copyright_xml | – notice: 2016 American Heart Association, Inc. – notice: Distributed under a Creative Commons Attribution 4.0 International License |
| CorporateAuthor | on behalf of the IMPROVE Study Group |
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| Issue | 9 |
| Keywords | actin cytoskeleton atherosclerosis smooth muscle cells hyperplasia downregulation |
| Language | English |
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| PublicationTitle | Arteriosclerosis, thrombosis, and vascular biology |
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| Snippet | OBJECTIVE—Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems... Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology... Objective— Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems... |
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| SubjectTerms | Actin Cytoskeleton - metabolism Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Animals Apolipoproteins E - deficiency Apolipoproteins E - genetics Atherosclerosis - genetics Atherosclerosis - metabolism Atherosclerosis - pathology Autoantigens - genetics Autoantigens - metabolism Calcium-Binding Proteins - genetics Calcium-Binding Proteins - metabolism Carotid Arteries - metabolism Carotid Arteries - pathology Carotid Arteries - physiopathology Carotid Artery Diseases - genetics Carotid Artery Diseases - metabolism Carotid Artery Diseases - pathology Carotid Artery Diseases - physiopathology Carotid Artery Injuries - genetics Carotid Artery Injuries - metabolism Case-Control Studies Cell Dedifferentiation Cells, Cultured Cytoskeletal Proteins - genetics Cytoskeletal Proteins - metabolism Disease Models, Animal Down-Regulation Genetic Association Studies Humans Intermediate Filament Proteins - genetics Intermediate Filament Proteins - metabolism Life Sciences LIM Domain Proteins - genetics LIM Domain Proteins - metabolism Male Mice, Knockout Microfilament Proteins - genetics Microfilament Proteins - metabolism Middle Aged Muscle, Smooth, Vascular - metabolism Muscle, Smooth, Vascular - pathology Muscle, Smooth, Vascular - physiopathology Myocytes, Smooth Muscle - metabolism Myocytes, Smooth Muscle - pathology Neointima Phenotype Plaque, Atherosclerotic Rats, Sprague-Dawley RNA Interference Signal Transduction Time Factors Transfection Vasoconstriction |
| Title | Phenotypic Modulation of Smooth Muscle Cells in Atherosclerosis Is Associated With Downregulation of LMOD1, SYNPO2, PDLIM7, PLN, and SYNM |
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