Analysis of arterial intimal hyperplasia: review and hypothesis

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: Despite a prodigious investment of funds, we cannot treat or prevent arteriosclerosis and restenosis, particularly its major pathology, arterial intimal hyperplasia. A cornerstone question lies behind all approaches to the disease: what causes the pathology? Hypothesis: I argue that the question itself is misplaced because it implies that intimal hyperplasia is a novel pathological phenomenon caused by new mechanisms. A simple inquiry into arterial morphology shows the opposite is true. The normal multi-layer cellular organization of the tunica intima is identical to that of diseased hyperplasia; it is the standard arterial system design in all placentals at least as large as rabbits, including humans. Formed initially as one-layer endothelium lining, this phenotype can either be maintained or differentiate into a normal multi-layer cellular lining, so striking in its resemblance to diseased hyperplasia that we have to name it "benign intimal hyperplasia". However, normal or "benign " intimal hyperplasia, although microscopically identical to pathology, is a controllable phenotype that rarely compromises blood supply. It is remarkable that each human heart has coronary arteries in which a single-layer endothelium differentiates earl

Fibulin-4 regulates expression of the tropoelastin gene and consequent elastic-fibre formation by human fibroblasts

Elastic fibres are essential for normal physiology in numerous tissues, including arteries, lungs and skin. Fibulin-4 is an elastic-fibre-associated glycoprotein that is indispensable for elastic-fibre formation in mice. However, the mechanism by which fibulin-4 executes this function remains to be determined. Here, we established an in vitro functional assay system in which fibulin-4 was knocked down in human foreskin fibroblasts using siRNA (small interfering RNA) technology. With two different siRNAs, substantial knockdown of fibulin-4 was achieved, and this suppression was associated with impaired elastic-fibre formation by the fibroblasts. Real-time reverse transcription–PCR analysis showed that knockdown of fibulin-4 expression was accompanied by reduced expression of tropoelastin mRNA. Further analysis showed that this decrease was caused by transcriptional down-regulation of tropoelastin. This effect was selective, since the mRNA level of other elastic-fibre-associated proteins, including fibrillin-1, lysyl oxidase and lysyl oxidase-like-1, was not affected. Moreover, addition of conditioned medium from cultures of CHO (Chinese-hamster ovary) cells overexpressing fibulin-4 stimulated tropoelastin expression and elastic-fibre formation in cultures of Williams–Beuren-syndrome fibroblasts. Knocking down or knocking out fibulin-4 in mice led to a decrease in tropoelastin expression in the aorta. These results indicate that fibulin-4, considered as a structural protein, may also participate in regulating elastic-fibre formation in human cells through an unanticipated mechanism, namely the regulation of tropoelastin expression