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Crosstalk between CD248 and PDGFR? Regulates the pathogenic role of smooth muscle cells in atherosclerosis
Abstracts / Atherosclerosis 241 (2015) e32ee71
EAS-0641. THE ABSENCE OF THE EDA ALTERNATIVE SPLICED ISOFORM OF FIBRONECTIN PROMOTES SMOOTH MUSCLE CELLS MIGRATION AND RESULTS IN NEO-INTIMAL HYPERPLASIA A. Dhyani, V. Pulakazhi Venu, R. Baetta, P. Uboldi, N. Ferri, A. Corsini, A. Muro, A. Catapano, G. Norata. Department of Pharmacological and degli studi di Milano, Milano, Italy Biomolecular Sciences, Universita Aim: The two most relevant isoforms of Fibronectin in the context of vascular biology are those expressing (EDA+/+) or lacking (EDA-/-) the extra domain-A (EDA).Here, we investigated the role of FN-EDA in vascular smooth muscle cells biology and neointima formation. Methods: Mice engineered to always generate EDA-containing Fibronectin or constitutively lacking EDA in FN (EDA-/-) were compared to Wild type mice which generates both isoforms of fibronectin.2 months old mice undergone surgery to place non-obstructive collar in the right carotid for a period of 9 weeks.In parallel the characterization of VSMCs isolated from mice aorta was performed. Results: Neo-intima formation was investigated in the carotid arteries of all three mice types.EDA-/- lines of mice have presented a significant increased intima-media thickness(IMT) compared to EDA+/+ and EDA-WT (1.472, 0.8541 and 1.095 mm, p<0.05, respectively).Molecular markers representing the contractile and synthetic phenotypes of the vascular smooth muscle cells were also evaluated. Smemb, Myocardin and Klf-4 were found higher among EDA-/- mice in comparison to the EDA+/+ and EDA-WT. VSMCs migration pattern were found higher among EDA-/-cells when compared with EDA+/+ cells at different time points 0hr, 8hr and 24 hr (EDA -/- vs EDA +/+ cells for 8 hrs- 61% ± 20% vs 23% ± 2% ; for 24 hrs100 % ± 0% vs 75% ± 18%).In addition, pERK, and pAKT activity were also found higher among EDA-/- cells when compared with EDA +/+ cells type. Conclusion: The absence of EDA inclusion in fibronectin promotes increased VSMCs proliferation, migration and favors neo-intimal hyperplasia.
EAS-0702. CROSSTALK BETWEEN CD248 AND PDGFR? REGULATES THE PATHOGENIC ROLE OF SMOOTH MUSCLE CELLS IN ATHEROSCLEROSIS M. Harrison 1, A.J. Naylor 2, B. Apta 1, C. Monaco 3, C.D. Buckley 2, G.E. Rainger 1. 1 Clinical & Experimental Medicine, University of Birmingham, Birmingham, United Kingdom; 2 Immunity & Infection, University of Birmingham, Birmingham, United Kingdom; 3 Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom Atherosclerosis is a chronic inflammatory disease of the artery wall, characterised by the development of lipid laden plaques, which are complex in both their molecular and cellular nature. Smooth muscle cells (SMC) play a prominent role in plaque progression, undergoing mitogenic stimulation and becoming highly migratory and proliferative. Secretory SMC invade the intimal layer of the diseased artery, where they proliferate and generate a number of pro-inflammatory agents, culminating in leukocyte infiltration of the artery wall. CD248 (endosialin) is a 175000 molecular weight type-1 transmembrane receptor whose ligands are reported to be extracellular matrix molecules; fibronectin and collagen type I/IV. CD248 is widely expressed on mesenchymal cells in the developing embryo; however, expression of CD248 is dramatically reduced in the adult but is upregulated during fibrosis, inflammation and malignancy. Recent work has indicated that CD248 is required for effective signalling through platelet-derived growth factor (PDGF) receptor b, which acts as a potent regulator of SMC and pericyte function, indicating that CD248 could potentially be involved in the progression of atherosclerosis. In the current study, we found high expression of CD248 in human carotid plaques. In addition, human atherosclerotic SMC derived from diseased tissue demonstrated increased migration to PDGF in vitro compared to heathy controls. In vivo, plaque burden was significantly decreased in
e45
CD248-/- ApoE-/- mice compared to ApoE-/- . These data strongly imply that crosstalk between CD248 and PDGFRb has the ability to regulate the pathogenic role of smooth muscle cells in the development of atherosclerosis.
EAS-0931. DIMINAZENE ENHANCES STABLE PHENOTYPE OF ATHEROSCLEROTIC PLAQUES R. Fraga-Silva 1, F. Montecucco 2, F.P. Costa-Fraga 1, F. Mach 2, R.A.S. Santos 3, R.F. Silva 3, N. Stergiopulos 1. 1 Institute of Bioengineering, Ecole Polytechnique F ed erale de Lausanne, Lausanne, Switzerland; 2 Division of Cardiology Faculty of Medicine Foundation for Medical Researches, University of Geneva, Geneva, Switzerland; 3 Physiology, Federal University of Minas Gerais, Belo Horizonte, Brazil Aim: Angiotensin (Ang) II contributes to the progression of atherosclerosis, while Ang-(1-7) has atheroprotective actions. Likewise, angiotensin-converting enzyme 2 (ACE2), an enzyme which breaks-down Ang II and forms Ang-(1-7), reduces atherosclerotic plaque size and vulnerability, being suggested as a potential target against atherosclerosis. Here we aimed to investigate the effects of diminazene, a recently developed ACE2 activator compound, in a mouse model of vulnerable atherosclerotic plaque. Methods: ApoE gene-deleted mice were fed with western-type diet for 11 weeks. Atherosclerotic plaque formation was induced in the carotid artery by a shear stress modifier device, which expose the vessel to a low and oscillatory shear stress. The mice were treated with diminazene (15 mg/ Kg/day) or vehicle for the last 3 weeks. The plaques composition was analyzed. Results: ACE2 was well expressed in the aortic root and low shear stressinduced carotid plaques, but not detected in the oscillatory shear stressinduced carotid plaques. Diminazene treatment did not change the lesion size, but ameliorates the composition of aortic root and low shear stressinduced carotid plaques by increasing collagen content and decreasing MMPs expression and cell infiltration. However, these beneficial effects were not observed in the oscillatory shear stress-induced plaque. Additionally, diminazene treatment decreased serum triglycerides level but not changed total cholesterol, LDL, HDL or FFA. Conclusions: ACE2, a major enzyme of the renin angiotensin system, is differently expressed in atherosclerotic plaques, depending on the local pattern of shear stress forces. Moreover, treatment with diminazene enhances the stable phenotype of atherosclerotic plaques.
Insulin resistance, metabolic syndrome and obesity EAS-0165. BODY MASS INDEX SIGNIFICANTLY MODULATES THE POWER OF CREACTIVE PROTEIN TO PREDICT CARDIOVASCULAR EVENT RISK AMONG ANGIOGRAPHIED CORONARY PATIENTS A. Vonbank 1, C.H. Saely 1, D. Zanolin 2, P. Rein 1, A. Leiherer 2, H. Drexel 1. 1 Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria; 2 VIVIT-Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria Aim: Epidemiological studies in various populations show that obesity is associated with inflammation and with increased cardiovascular risk, and that the inflammatory marker C-reactive protein (CRP) strongly predicts the incidence of cardiovascular events. Whether CRP is equally predictive of cardiovascular event risk in obese patients and in non-obese subjects is not known and is addressed in the present study. Methods: Cardiovascular events were recorded over a follow-up period of 10 years in a large high-risk population of 1,731 consecutive patients undergoing coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD). Obesity was defined as body mass index (BMI) 30kg/m2.
EAS-0641. THE ABSENCE OF THE EDA ALTERNATIVE SPLICED ISOFORM OF FIBRONECTIN PROMOTES SMOOTH MUSCLE CELLS MIGRATION AND RESULTS IN NEO-INTIMAL HYPERPLASIA A. Dhyani, V. Pulakazhi Venu, R. Baetta, P. Uboldi, N. Ferri, A. Corsini, A. Muro, A. Catapano, G. Norata. Department of Pharmacological and degli studi di Milano, Milano, Italy Biomolecular Sciences, Universita Aim: The two most relevant isoforms of Fibronectin in the context of vascular biology are those expressing (EDA+/+) or lacking (EDA-/-) the extra domain-A (EDA).Here, we investigated the role of FN-EDA in vascular smooth muscle cells biology and neointima formation. Methods: Mice engineered to always generate EDA-containing Fibronectin or constitutively lacking EDA in FN (EDA-/-) were compared to Wild type mice which generates both isoforms of fibronectin.2 months old mice undergone surgery to place non-obstructive collar in the right carotid for a period of 9 weeks.In parallel the characterization of VSMCs isolated from mice aorta was performed. Results: Neo-intima formation was investigated in the carotid arteries of all three mice types.EDA-/- lines of mice have presented a significant increased intima-media thickness(IMT) compared to EDA+/+ and EDA-WT (1.472, 0.8541 and 1.095 mm, p<0.05, respectively).Molecular markers representing the contractile and synthetic phenotypes of the vascular smooth muscle cells were also evaluated. Smemb, Myocardin and Klf-4 were found higher among EDA-/- mice in comparison to the EDA+/+ and EDA-WT. VSMCs migration pattern were found higher among EDA-/-cells when compared with EDA+/+ cells at different time points 0hr, 8hr and 24 hr (EDA -/- vs EDA +/+ cells for 8 hrs- 61% ± 20% vs 23% ± 2% ; for 24 hrs100 % ± 0% vs 75% ± 18%).In addition, pERK, and pAKT activity were also found higher among EDA-/- cells when compared with EDA +/+ cells type. Conclusion: The absence of EDA inclusion in fibronectin promotes increased VSMCs proliferation, migration and favors neo-intimal hyperplasia.
EAS-0702. CROSSTALK BETWEEN CD248 AND PDGFR? REGULATES THE PATHOGENIC ROLE OF SMOOTH MUSCLE CELLS IN ATHEROSCLEROSIS M. Harrison 1, A.J. Naylor 2, B. Apta 1, C. Monaco 3, C.D. Buckley 2, G.E. Rainger 1. 1 Clinical & Experimental Medicine, University of Birmingham, Birmingham, United Kingdom; 2 Immunity & Infection, University of Birmingham, Birmingham, United Kingdom; 3 Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom Atherosclerosis is a chronic inflammatory disease of the artery wall, characterised by the development of lipid laden plaques, which are complex in both their molecular and cellular nature. Smooth muscle cells (SMC) play a prominent role in plaque progression, undergoing mitogenic stimulation and becoming highly migratory and proliferative. Secretory SMC invade the intimal layer of the diseased artery, where they proliferate and generate a number of pro-inflammatory agents, culminating in leukocyte infiltration of the artery wall. CD248 (endosialin) is a 175000 molecular weight type-1 transmembrane receptor whose ligands are reported to be extracellular matrix molecules; fibronectin and collagen type I/IV. CD248 is widely expressed on mesenchymal cells in the developing embryo; however, expression of CD248 is dramatically reduced in the adult but is upregulated during fibrosis, inflammation and malignancy. Recent work has indicated that CD248 is required for effective signalling through platelet-derived growth factor (PDGF) receptor b, which acts as a potent regulator of SMC and pericyte function, indicating that CD248 could potentially be involved in the progression of atherosclerosis. In the current study, we found high expression of CD248 in human carotid plaques. In addition, human atherosclerotic SMC derived from diseased tissue demonstrated increased migration to PDGF in vitro compared to heathy controls. In vivo, plaque burden was significantly decreased in
e45
CD248-/- ApoE-/- mice compared to ApoE-/- . These data strongly imply that crosstalk between CD248 and PDGFRb has the ability to regulate the pathogenic role of smooth muscle cells in the development of atherosclerosis.
EAS-0931. DIMINAZENE ENHANCES STABLE PHENOTYPE OF ATHEROSCLEROTIC PLAQUES R. Fraga-Silva 1, F. Montecucco 2, F.P. Costa-Fraga 1, F. Mach 2, R.A.S. Santos 3, R.F. Silva 3, N. Stergiopulos 1. 1 Institute of Bioengineering, Ecole Polytechnique F ed erale de Lausanne, Lausanne, Switzerland; 2 Division of Cardiology Faculty of Medicine Foundation for Medical Researches, University of Geneva, Geneva, Switzerland; 3 Physiology, Federal University of Minas Gerais, Belo Horizonte, Brazil Aim: Angiotensin (Ang) II contributes to the progression of atherosclerosis, while Ang-(1-7) has atheroprotective actions. Likewise, angiotensin-converting enzyme 2 (ACE2), an enzyme which breaks-down Ang II and forms Ang-(1-7), reduces atherosclerotic plaque size and vulnerability, being suggested as a potential target against atherosclerosis. Here we aimed to investigate the effects of diminazene, a recently developed ACE2 activator compound, in a mouse model of vulnerable atherosclerotic plaque. Methods: ApoE gene-deleted mice were fed with western-type diet for 11 weeks. Atherosclerotic plaque formation was induced in the carotid artery by a shear stress modifier device, which expose the vessel to a low and oscillatory shear stress. The mice were treated with diminazene (15 mg/ Kg/day) or vehicle for the last 3 weeks. The plaques composition was analyzed. Results: ACE2 was well expressed in the aortic root and low shear stressinduced carotid plaques, but not detected in the oscillatory shear stressinduced carotid plaques. Diminazene treatment did not change the lesion size, but ameliorates the composition of aortic root and low shear stressinduced carotid plaques by increasing collagen content and decreasing MMPs expression and cell infiltration. However, these beneficial effects were not observed in the oscillatory shear stress-induced plaque. Additionally, diminazene treatment decreased serum triglycerides level but not changed total cholesterol, LDL, HDL or FFA. Conclusions: ACE2, a major enzyme of the renin angiotensin system, is differently expressed in atherosclerotic plaques, depending on the local pattern of shear stress forces. Moreover, treatment with diminazene enhances the stable phenotype of atherosclerotic plaques.
Insulin resistance, metabolic syndrome and obesity EAS-0165. BODY MASS INDEX SIGNIFICANTLY MODULATES THE POWER OF CREACTIVE PROTEIN TO PREDICT CARDIOVASCULAR EVENT RISK AMONG ANGIOGRAPHIED CORONARY PATIENTS A. Vonbank 1, C.H. Saely 1, D. Zanolin 2, P. Rein 1, A. Leiherer 2, H. Drexel 1. 1 Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria; 2 VIVIT-Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria Aim: Epidemiological studies in various populations show that obesity is associated with inflammation and with increased cardiovascular risk, and that the inflammatory marker C-reactive protein (CRP) strongly predicts the incidence of cardiovascular events. Whether CRP is equally predictive of cardiovascular event risk in obese patients and in non-obese subjects is not known and is addressed in the present study. Methods: Cardiovascular events were recorded over a follow-up period of 10 years in a large high-risk population of 1,731 consecutive patients undergoing coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD). Obesity was defined as body mass index (BMI) 30kg/m2.