Apelin; Macrophages; S100A4; Restenosis; Smooth muscle cells; Calmodulin; Atherosclerosis
Bochaton-Piallat Marie-Luce, Gabbiani Giulio, Hinz Boris (2016), The myofibroblast in wound healing and fibrosis: answered and unanswered questions., in F1000Research
, 5, 1-6.
Chaabane Chiraz, Heizmann Claus W, Bochaton-Piallat Marie-Luce (2015), Extracellular S100A4 induces smooth muscle cell phenotypic transition mediated by RAGE., in Biochimica et biophysica acta
, 1853(9), 2144-57.
Kutkut Issa, Meens Merlijn J, McKee Thomas A, Bochaton-Piallat Marie-Luce, Kwak Brenda R (2015), Lymphatic vessels: an emerging actor in atherosclerotic plaque development., in European journal of clinical investigation
, 45(1), 100-8.
Prunotto Marco, Bruschi Maurizio, Gunning Peter, Gabbiani Giulio, Weibel Franziska, Ghiggeri Gian Marco, Petretto Andrea, Scaloni Andrea, Bonello Teresa, Schevzov Galina, Alieva Irina, Bochaton-Piallat Marie-Luce, Candiano Giovanni, Dugina Vera, Chaponnier Christine (2015), Stable incorporation of α-smooth muscle actin into stress fibers is dependent on specific tropomyosin isoforms., in Cytoskeleton (Hoboken, N.J.)
, 72(6), 257-67.
Chaabane Chiraz, Coen Matteo, Bochaton-Piallat Marie-Luce (2014), Smooth muscle cell phenotypic switch: implications for foam cell formation., in Current opinion in lipidology
, 25(5), 374-9.
Chaabane Chiraz, Otsuka Fumiyuki, Virmani Renu, Bochaton-Piallat Marie-Luce (2013), Biological responses in stented arteries., in Cardiovascular research
, 99(2), 353-63.
Coen Matteo, Marchetti Giovanna, Palagi Patricia M, Zerbinati Carlotta, Guastella Giuseppe, Gagliano Teresa, Bernardi Francesco, Mascoli Francesco, Bochaton-Piallat Marie-Luce (2013), Calmodulin expression distinguishes the smooth muscle cell population of human carotid plaque., in The American journal of pathology
, 183(3), 996-1009.
During atherosclerosis and restenosis, smooth muscle cells (SMCs) accumulate into the intima and undergo phenotypic changes. It has been proposed that SMCs from the arterial wall are phenotypically heterogeneous and hence that a subset of medial SMCs is prone to accumulate into the intima. The major goal of our research is to identify biomarkers typical of the atheroma-prone phenotype and subsequently to explore their role in the phenotypic modulation of intimal SMCs. We have isolated two distinct SMC populations, spindle-shaped (S) and rhomboid (R) SMCs, from the porcine coronary artery. R-SMCs display the features of an atheroma-prone phenotype. We have identified S100A4, a calcium-binding protein, as being a marker of the R-SMC population in vitro and of intimal SMCs, both in pig and man.Aim 1. We have demonstrated that the extracellular form of S100A4 is essential for the establishment of the R-phenotype and acts, to some extent, through the receptor for advanced glycation end products RAGE. In the frame of this grant application, we will characterize signaling pathways and genes involved in SMC phenotypic transition by means of microarray analysis comparing S-SMCs treated with conditioned medium containing or not extracellular S100A4. Our preliminary results show that 23 genes exhibit more than 10-fold increase. We will first focus our studies on the lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) and on its role in SMC phenotypic changes. Codependence between RAGE/LOX-1 will be also explored. We have developed the tools to study and modulate SMC phenotypic changes, S100A4 and RAGE expression.Aim 2. Apelin is a small peptide hitherto poorly studied in SMCs. We have observed a nuclear expression of apelin in R-SMCs. Transfection of a plasmid containing nuclear-targeting apelin in S-SMCs (devoid of apelin) induces a phenotypic transition toward a R-phenotype, which is associated with increased nuclear expression of intracellular S100A4. We will confirm these unexpected results by thoroughly characterizing the SMC phenotypic changes induced by nuclear apelin overexpression and to clearly define whether apelin acts upstream S100A4. In parallel, we will explore the effect of secreted apelin in SMC phenotypic changes. Actin isoforms reveal a diverse organization in both SMC phenotypes. Therefore we will explore the relocalization of intracellular S100A4, from a stress-fiber like organization to a more diffuse pattern, by means of double immunofluorescence staining followed by confocal analysis using specific actin isoform antibodies and anti-S100A4.Aim 3. We have isolated two distinct SMC populations, small and large, from the media of human carotid arteries and observed that atherosclerotic plaque-derived macrophages promote selective migration of small SMCs, which represent an atheroma-prone phenotype. Moreover plaque-derived macrophages induce the large to small phenotypic transition. Calmodulin is overexpressed in small SMCs and plays a role in SMC phenotypic changes. In the frame of this grant, by using cytokine arrays, we plan to identify cytokine(s)/growth factor(s) released by plaque-derived macrophages, which are involved in the selective recruitment of small SMCs from the media and/or the large-to-small phenotypic transition. Once identified, the role of different cytokine(s) on SMC phenotypic modulation will be investigated.Aim 4. The relevance of molecules studied and identified in aims 1, 2 3 will be tested on human tissue specimens thanks to our network of collaboration with expert cardiovascular pathologist.Taken together, our results suggest that a better understanding of S100A4 expression, release and regulation in SMCs will help to shed light on the mechanisms of SMC accumulation in the intima. The identification of cytokines released by plaque-derived macrophages should help in dissecting the mechanisms of the crosstalk between macrophages and SMCs. The ultimate aim of our work is the development of tools to influence the evolution of atherosclerotic and restenotic lesions.