Apolipoprotein D and platelet-derived growth factor-BB synergism mediates vascular smooth muscle cell migration.

We identified apolipoprotein (apo)D in a search for proteins upregulated in a posttranscriptional manner similar to fibronectin in motile smooth muscle cells (SMCs). To address the function of apoD in SMCs, we cloned a partial apoD cDNA from ovine aortic (Ao) SMCs using RT-PCR. We documented a 2.5-fold increase in apoD protein but no increase in apoD mRNA in Ao SMCs 48 hours after a multiwound migration assay (P<0.01). Confocal microscopy revealed prominent perinuclear and trailing edge expression of apoD in migrating SMCs but not in the confluent monolayer. Stimulation of Ao SMCs with 10 ng/mL platelet-derived growth factor (PDGF)-BB increased apoD protein expression (P<0.05). Moreover, PDGF-BB-stimulated migration of human pulmonary artery SMCs was suppressed by knock-down of apoD using RNAi. Stable overexpression of apoD in Ao SMCs cultured in 10% fetal bovine serum promoted random migration by 62% compared with vector-transfected cells (P<0.01). Overexpression of apoD or addition of exogenous apoD to a rat aortic SMC line (A10) stimulated their migration in response to a subthreshold dose of PDGF-BB (P<0.05). This was unrelated to increased phosphorylation of ERK1/2 or of phospholipase C-gamma1, but correlated with enhanced Rac1 activation. This study shows that apoD can be expressed or taken up by SMCs and can regulate their motility in response to growth factors.

Apolipoprotein D inhibits platelet-derived growth factor-BB-induced vascular smooth muscle cell proliferated by preventing translocation of phosphorylated extracellular signal regulated kinase 1/2 to the nucleus.

OBJECTIVE: Elevated apolipoprotein D (apoD) levels are associated with reduced proliferation of cancer cells. We therefore investigated whether apoD, which occurs free or associated with HDL, suppresses vascular smooth muscle cell (VSMC) proliferation, which is related to the pathobiology of disease. METHODS AND RESULTS: Intense immunoreactivity for apoD was observed in human atherosclerotic plaque but not in normal coronary artery. However, an increase in apoD mRNA was seen in quiescent relative to proliferating fetal lamb aortic VSMCs, and in the rat aortic VSMC line (A10), we demonstrated uptake of apoD from serum. Stable transfection of apoD in A10 cells in the absence of serum did not influence VSMC proliferation assessed by [3H]-thymidine incorporation. ApoD, administered at a dose of 100 ng/mL, completely inhibited basal as well as platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation (P<0.01) but had no effect on fibroblast growth factor-induced VSMC proliferation. ApoD did not suppress PDGF-BB or fibroblast growth factor-2-induced phosphorylation of extracellular signal regulated kinase (ERK) 1/2 but selectively inhibited PDGF-BB-mediated ERK1/2 nuclear translocation. CONCLUSIONS: Our data suggest that apoD selectively modulates the proliferative response of VSMC to growth factors by a mechanism related to nuclear translocation of ERK1/2.

Cancer of the heart: epidemiology and management of primary tumors and metastases.

Cardiac tumors, benign or malignant, are rare and most are benign. The most common benign tumor is the cardiac myxoma. Malignant cardiac tumors are usually sarcomas. The pericardium can be the site of benign and malignant cardiac tumors, though metastatic tumors occur here far more commonly than do primary tumors. Successful treatment for benign cardiac tumors is usually achieved by surgical resection. Surgery for primary malignant tumors is, however, much less successful as complete resection is usually not possible. Primary cardiac lymphoma may be successfully treated by chemotherapy. Tumors that metastasize to the heart from other organs occur 100- to 1000-fold more commonly than primary cardiac tumors. Metastatic spread to the heart has been identified in approximately one-fifth of all patients who have metastatic cancer with lung carcinoma being the most common primary tumor. Symptoms of cardiac metastases vary, and they depend on the site and extent of the lesions. Treatment varies depending on the pathology of the primary tumor. However, the aim of treatment is usually symptomatic relief. With the advent of AIDS, Kaposi's sarcoma and high grade B cell lymphomas have also been identified in cardiac tissue. The aim of this article is to review the epidemiology, clinical presentation, pathology and treatment of cardiac tumors.

Understanding and treating vein graft atherosclerosis.

BACKGROUND: Vein grafts have been used as bypass conduits for coronary artery disease since the 1960s. This widely used treatment, however, is complicated by the development of changes in the vein graft, which resemble atherosclerosis and are often termed as such. They occur at about 10 years, which leads to the need for reoperation in some patients. The purpose of this review is to summarize the knowledge regarding the pathophysiology of vein graft "atherosclerosis," as well as promising new treatments for this disease. METHODS: The relevant literature relating to the epidemiology, histology, cell and molecular pathophysiology and treatment of vein graft atherosclerosis is reviewed. RESULTS: The development of vein graft atherosclerosis differs from arterial atherosclerosis. Studies have examined the role of trauma, lipids, vasoactive mediators, smooth muscle cell mitogens, smooth muscle cells apoptosis, adhesion molecules and proteases. Therapies have been developed to prevent vein graft atherosclerosis based on these studies and have been tested using animal models and in patients. DISCUSSION: Promising new therapies have been developed based on current knowledge and further applications of genomics will allow for the further identification of risk factors and mechanistic insights. The use of arterial grafts such as the internal mammary artery, which have higher patency rates at 10 years compared with vein grafts as well as approaches to revascularize infarcted myocardium may one day replace the use of vascular conduits.