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Profilin-1 is expressed in human atherosclerotic plaques and induces atherogenic effects on vascular smooth muscle cells.

Caglayan E, Romeo GR, Kappert K, Odenthal M, Südkamp M, Body SC, Shernan SK, Hackbusch D, Vantler M, Kazlauskas A, Rosenkranz S - PLoS ONE (2010)

Bottom Line: In coronary arteries from patients with coronary heart disease, we found markedly enhanced profilin expression in atherosclerotic plaques compared to the normal vessel wall.Inhibition of PI3K (Wortmannin, LY294002) or Src-family kinases (SU6656, PP2), but not PLCγ (U73122), completely abolished profilin-induced cell cycle progression, whereas PI3K inhibition partially reduced the chemotactic response.The atherogenic effects exerted by profilin-1 on VSMCs suggest an auto-/paracrine role within the plaque.

View Article: PubMed Central - PubMed

Affiliation: Klinik III für Innere Medizin, Universität zu Köln, Cologne, Germany.

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 PLCγ (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.

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Correlation between the degree of aortic atherosclerosis and profilin-1 serum levels.In 104 patients undergoing CABG, the degree of aortic atherosclerosis was assessed by intraoperative ultrasound at 33 points along the arch, thoracic and abdominal aorta. According to the 33-point ultrasound score, individuals were clustered into three categories (0–7 = None; 8–20 = Mixed; 21–33 = Severe). The control group is represented by 18 individuals without major diagnosed diseases. Shown is a dot plot, the bar representing the mean in each group. p<0.001 between the ‘Severe’ group and the ‘Control’ or ‘None’ group.
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pone-0013608-g006: Correlation between the degree of aortic atherosclerosis and profilin-1 serum levels.In 104 patients undergoing CABG, the degree of aortic atherosclerosis was assessed by intraoperative ultrasound at 33 points along the arch, thoracic and abdominal aorta. According to the 33-point ultrasound score, individuals were clustered into three categories (0–7 = None; 8–20 = Mixed; 21–33 = Severe). The control group is represented by 18 individuals without major diagnosed diseases. Shown is a dot plot, the bar representing the mean in each group. p<0.001 between the ‘Severe’ group and the ‘Control’ or ‘None’ group.

Mentions: Importantly, we also assessed whether the serum levels of profilin-1 were associated with the degree of atherosclerosis in humans. To this end, patients undergoing coronary bypass surgery were evaluated for the presence and severity of aortic atherosclerosis by intraoperative ultrasound at 33 points along the arch, thoracic and abdominal aorta, and the atherosclerosis score was correlated to profilin-1 serum levels. We found that profilin levels were significantly elevated in patients with the most severe aortic atherosclerosis score (Figure 6), indicating that profilin-1 serum levels were associated with the degree of atherosclerosis in humans.


Profilin-1 is expressed in human atherosclerotic plaques and induces atherogenic effects on vascular smooth muscle cells.

Caglayan E, Romeo GR, Kappert K, Odenthal M, Südkamp M, Body SC, Shernan SK, Hackbusch D, Vantler M, Kazlauskas A, Rosenkranz S - PLoS ONE (2010)

Correlation between the degree of aortic atherosclerosis and profilin-1 serum levels.In 104 patients undergoing CABG, the degree of aortic atherosclerosis was assessed by intraoperative ultrasound at 33 points along the arch, thoracic and abdominal aorta. According to the 33-point ultrasound score, individuals were clustered into three categories (0–7 = None; 8–20 = Mixed; 21–33 = Severe). The control group is represented by 18 individuals without major diagnosed diseases. Shown is a dot plot, the bar representing the mean in each group. p<0.001 between the ‘Severe’ group and the ‘Control’ or ‘None’ group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2963617&req=5

pone-0013608-g006: Correlation between the degree of aortic atherosclerosis and profilin-1 serum levels.In 104 patients undergoing CABG, the degree of aortic atherosclerosis was assessed by intraoperative ultrasound at 33 points along the arch, thoracic and abdominal aorta. According to the 33-point ultrasound score, individuals were clustered into three categories (0–7 = None; 8–20 = Mixed; 21–33 = Severe). The control group is represented by 18 individuals without major diagnosed diseases. Shown is a dot plot, the bar representing the mean in each group. p<0.001 between the ‘Severe’ group and the ‘Control’ or ‘None’ group.
Mentions: Importantly, we also assessed whether the serum levels of profilin-1 were associated with the degree of atherosclerosis in humans. To this end, patients undergoing coronary bypass surgery were evaluated for the presence and severity of aortic atherosclerosis by intraoperative ultrasound at 33 points along the arch, thoracic and abdominal aorta, and the atherosclerosis score was correlated to profilin-1 serum levels. We found that profilin levels were significantly elevated in patients with the most severe aortic atherosclerosis score (Figure 6), indicating that profilin-1 serum levels were associated with the degree of atherosclerosis in humans.

Bottom Line: In coronary arteries from patients with coronary heart disease, we found markedly enhanced profilin expression in atherosclerotic plaques compared to the normal vessel wall.Inhibition of PI3K (Wortmannin, LY294002) or Src-family kinases (SU6656, PP2), but not PLCγ (U73122), completely abolished profilin-induced cell cycle progression, whereas PI3K inhibition partially reduced the chemotactic response.The atherogenic effects exerted by profilin-1 on VSMCs suggest an auto-/paracrine role within the plaque.

View Article: PubMed Central - PubMed

Affiliation: Klinik III für Innere Medizin, Universität zu Köln, Cologne, Germany.

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 PLCγ (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.

Show MeSH
Related in: MedlinePlus