Universität zu Köln

Caglayan, Evren, Romeo, Giulio R., Kappert, Kai ORCID: 0000-0001-6976-0428, Odenthal, Margarete, Suedkamp, Michael, Body, Simon C., Shernan, Stanton K., Hackbusch, Daniel, Vantler, Marius, Kazlauskas, Andrius and Rosenkranz, Stephan (2010). Profilin-1 Is Expressed in Human Atherosclerotic Plaques and Induces Atherogenic Effects on Vascular Smooth Muscle Cells. PLoS One, 5 (10). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Background: Profilin-1 is an ubiquitous actin binding protein. Under pathological conditions such as diabetes, profilin-1 levels are increased in the vascular endothelium. We recently demonstrated that profilin-1 overexpression triggers indicators of endothelial dysfunction downstream of LDL signaling, and that attenuated expression of profilin-1 confers protection from atherosclerosis in vivo. Methodology: Here we monitored profilin-1 expression in human atherosclerotic plaques by immunofluorescent staining. The effects of recombinant profilin-1 on atherogenic signaling pathways and cellular responses such as DNA synthesis (BrdU-incorporation) and chemotaxis (modified Boyden-chamber) were evaluated in cultured rat aortic and human coronary vascular smooth muscle cells (VSMCs). Furthermore, the correlation between profilin-1 serum levels and the degree of atherosclerosis was assessed in humans. Principal Findings: In coronary arteries from patients with coronary heart disease, we found markedly enhanced profilin expression in atherosclerotic plaques compared to the normal vessel wall. Stimulation of rat aortic and human coronary VSMCs with recombinant profilin-1 (10(-6) M) in vitro led to activation of intracellular signaling cascades such as phosphorylation of Erk1/2, p70(S6) kinase and PI3K/Akt within 10 minutes. Furthermore, profilin-1 concentration-dependently induced DNA-synthesis and migration of both rat and human VSMCs, respectively. Inhibition of PI3K (Wortmannin, LY294002) or Src-family kinases (SU6656, PP2), but not PLC gamma (U73122), completely abolished profilin-induced cell cycle progression, whereas PI3K inhibition partially reduced the chemotactic response. Finally, we found that profilin-1 serum levels were significantly elevated in patients with severe atherosclerosis in humans (p<0.001 vs. no atherosclerosis or control group). Conclusions: Profilin-1 expression is significantly enhanced in human atherosclerotic plaques compared to the normal vessel wall, and the serum levels of profilin-1 correlate with the degree of atherosclerosis in humans. The atherogenic effects exerted by profilin-1 on VSMCs suggest an auto-/paracrine role within the plaque. These data indicate that profilin-1 might critically contribute to atherogenesis and may represent a novel therapeutic target.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Caglayan, Evren UNSPECIFIED UNSPECIFIED UNSPECIFIED Romeo, Giulio R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kappert, Kai UNSPECIFIED orcid.org/0000-0001-6976-0428 UNSPECIFIED Odenthal, Margarete UNSPECIFIED UNSPECIFIED UNSPECIFIED Suedkamp, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Body, Simon C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Shernan, Stanton K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hackbusch, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Vantler, Marius UNSPECIFIED UNSPECIFIED UNSPECIFIED Kazlauskas, Andrius UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosenkranz, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-494138
DOI:	10.1371/journal.pone.0013608
Journal or Publication Title:	PLoS One
Volume:	5
Number:	10
Date:	2010
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACTIVATED RECEPTOR-GAMMA; ACTIN-BINDING PROTEIN; RAT MESANGIAL CELLS; GROWTH-FACTOR; INSULIN-RESISTANCE; DNA-SYNTHESIS; CHEMOTAXIS; INFLAMMATION; DYSFUNCTION; DISEASE Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/49413