Profilin-1 Is Expressed in Human Atherosclerotic Plaques and Induces Atherogenic Effects on Vascular Smooth Muscle Cells

Abstract

BackgroundProfilin-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.MethodologyHere 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 FindingsIn 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, p70S6 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).ConclusionsProfilin-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.

The multifaceted role of profilin-1 in adipose tissue inflammation and glucose homeostasis

“…Pfn can be detected in the human serum under normal conditions; also, pfn serum levels positively correlate with the degree of aortic atherosclerosis in patients with coronary artery disease. 43 In the same study, we demonstrated that extracellular pfn could induce such proatherogenic events as cell proliferation and chemotaxis. 43 Extracellular pfn was also detected in an experimental model of glomerulonephritis.…”

“…43 In the same study, we demonstrated that extracellular pfn could induce such proatherogenic events as cell proliferation and chemotaxis. 43 Extracellular pfn was also detected in an experimental model of glomerulonephritis. 44 What are the stimuli and mechanisms for pfn secretion, and is there a specific receptor/ligand on the cell membrane?…”

Profilin, and Vascular Diseases

“…In line with the established role of profilin in cellular migration and proliferation, it has been shown that recombinant profilin-I stimulates DNA-synthesis and migration of both rat and human VSMCs in a concentration-dependent manner (Caglayan et al, 2010). The same study indicated that profilin-induced VSMCs migration is dependent on PI3K activity (Caglayan et al, 2010).…”

“…The same study indicated that profilin-induced VSMCs migration is dependent on PI3K activity (Caglayan et al, 2010). Moreover, Cheng et al, (2011) found that profilin-I plays a key role in Angiotensin (Ang) II-induced VSMCs proliferation.…”

“…In this regard, profilins have been reported as major allergens implicated in pollen and food allergies in approximately 20% of type I allergy patients (Ebner et al, 1995;Valenta et al, 1991cValenta et al, , 1992. Furthermore, we (Hassona et al, 2010(Hassona et al, , 2011Moustafa-Bayoumi et al, 2007) and others (Caglayan et al, 2010;Romeo & Kazlauskas, 2008;Romeo et al, 2004Romeo et al, , 2007 have shown that profilin-I is an unexpectedly novel molecule that plays a highly significant role in vascular problems that predict a higher risk for developing arteriosclerosis, hypertension, stroke, heart failure, and finally death. Therefore, the aim of this chapter is to shed light on the significance of profilin-I via understanding the molecular and cellular aspects of this molecule, and its role in the vascular diseases.…”