Perivascular Adipose Tissue-Derived PDGF-D Contributes to Aortic Aneurysm Formation During Obesity.

Obesity increases the risk of vascular diseases, including aortic aneurysm (AA). Perivascular adipose tissue (PVAT) surrounding arteries are altered during obesity. However, the underlying mechanism of adipose tissue, especially PVAT, in the pathogenesis of AA is still unclear. Here we showed that angiotensin II (AngII) infusion increases the incidence of AA in leptin-deficient obese mice (ob/ob) and high-fat diet-induced obese mice with adventitial inflammation. Furthermore, transcriptome analysis revealed that platelet-derived growth factor-D (PDGF-D) was highly expressed in the PVAT of ob/ob mice. Therefore, we hypothesized that PDGF-D mediates adventitial inflammation, which provides a direct link between PVAT dysfunction and AA formation in AngII-infused obese mice. We found that PDGF-D promotes the proliferation, migration, and inflammatory factors expression in cultured adventitial fibroblasts. In addition, the inhibition of PDGF-D function significantly reduced the incidence of AA in AngII-infused obese mice. More importantly, adipocyte-specific PDGF-D transgenic mice are more susceptible to AA formation after AngII infusion accompanied by exaggerated adventitial inflammatory and fibrotic responses. Collectively, our findings reveal a notable role of PDGF-D in the AA formation during obesity, and modulation of this cytokine might be an exploitable treatment strategy for the condition.

Complex conserved organization of the mammalian leukemia inhibitory factor gene: regulated expression of intracellular and extracellular cytokines.

Leukemia inhibitory factor (LIF) is a member of the IL-6 family of pleiotropic cytokines, which are extensively involved in modulating hematopoiesis and immunity. We have undertaken a detailed analysis of LIF genomic organization and gene transcription and investigated the proteins expressed from alternate transcripts. Previously unidentified LIF transcripts, containing alternate first exons spliced onto common second and third exons, were cloned from murine embryonic stem cells, human embryonal carcinoma cells, and primary porcine fibroblasts. Based on sequence homology and position within the genomic sequence, this confirmed the existence of the LIF-M transcript in species other than the mouse and identified a new class of transcript, designated LIF-T. Thus, a complex genomic organization of the LIF gene, conserved among eutherian mammals, results in the expression of three LIF transcripts (LIF-D, LIF-M, and LIF-T) differentially expressed from alternate promoters. The first exon of the LIF-T transcript contained no in-frame AUG, causing translation to initiate downstream of the secretory signal sequence at the first AUG in exon two, producing a truncated LIF protein that was localized within the cell. Enforced secretion of this protein demonstrated that it could act as a LIF receptor agonist. Regulated expression of biologically active intracellular and extracellular LIF cytokine could thus provide alternate mechanisms for the modulation of hematopoiesis and immune system function.

Oncostatin M-specific receptor mediates inhibition of breast cancer cell growth and down-regulation of the c-myc proto-oncogene.

Human oncostatin M (OM) is a M(r) 28,000 glycoprotein that has been shown to regulate cell proliferation and differentiation. The biological activities of OM can be mediated by two different heterodimeric receptor complexes, the leukemia inhibitory factor (LIF)/OM shared receptor and the OM-specific receptor. In this study, we have examined the growth-regulatory effect of OM on 10 breast cancer cell lines derived from human tumors. The cellular proliferation of seven of these breast cancer cell lines was inhibited by OM. The three cell lines that did not respond to OM treatment lacked the expression of OM receptors. The growth-inhibitory activity of OM is examined further in the H3922 breast cancer cell line, which expresses the high-affinity OM receptor at a relatively higher level. We found that the cellular proliferation of H3922 cells was induced strongly by extrogenous epidermal growth factor (EGF), EGF-like factor, and basic fibroblast growth factor. The proliferative activities of these growth factors can be abolished totally by cotreatment of H3922 cells with OM. Treatment of H3922 cells with OM for 24 h did not block EGF binding or the induction of EGF receptor tyrosine phosphorylation. This finding suggests that OM interferes with the mitogenic signal at steps distal to the EGF receptor. Examination of proto-oncogene expression demonstrated that OM down-regulates the c-myc gene in H3922 cells. The biological effects reported herein are not shared by the OM-related cytokines interleukin 6 or LIF, as demonstrated by the inability of these proteins to inhibit cell growth or modulate c-myc gene expression in breast cancer cells. Additionally, the high-affinity binding of labeled OM cannot be displaced by LIF. Together, these data suggest that OM is a growth inhibitor for breast cancer cells. The inhibitory activity is mediated predominantly through the OM-specific receptor, and activation of this receptor abrogates growth factor stimulation and down-regulates the c-myc proto-oncogene.