Molecular Pathways of Endothelial Cell Activation for (Targeted) Pharmacological Intervention of Chronic Inflammatory Diseases

Abstract

In chronic inflammatory conditions, endothelial cells actively recruit immune cells from the circulation into the underlying tissue and participate in angiogenesis to support the continuous demand for oxygen and nutrients. They do so in response to activation by cytokines and growth factors such as tumour necrosis factor alpha (TNFalpha), interleukin-1 (IL-1), vascular endothelial growth factor (VEGF), and fibroblast growth factors (FGFs). Receptor triggering initiates intracellular signal transduction leading to activation of nuclear factor kappaB (NFkappaB), mitogen activated protein kinase (MAPK) activity, and nitric oxide and reactive oxygen species production, among others. As a result, adhesion molecules, cytokines and chemokines, and a variety of other genes are being expressed that mediate and control the inflammatory process. In recent years, different classes of drugs have been developed that interfere with selected enzymes involved in the intracellular signalling cascades. In endothelial cell cultures, they exert potent inhibitory effects on the expression of genes, while several studies also report on in vivo effectiveness to confine the inflammatory responses. To prevent undesired toxicity and to improve drug behaviour and efficacy, drug carrier systems have been developed that selectively deliver the therapeutics into the activated endothelial cells. The above subjects are recapitulated to give an overview on the status of development of endothelial cell directed therapeutic strategies to pharmacologically interfere with chronic inflammatory diseases.

Implications of Early Structural-Functional Changes in the Endothelium for Vascular Disease

“…46 Various classes of drugs are currently designed to act on specific enzymes involved in the intracellular signaling cascade in inflammation. 89 In addition, specific drugs that preclude the synthesis of different enzyme sources of ROS, such as vascular-specific NAD(P)H oxidase inhibitors, are efficient in prevention of EC dysfunction. 90 Superoxide dismutase entrapped in liposomes restores the EC-dependent relaxation, increases significantly the NO bioavailability, and is effective in scavenging superoxide anions in experimental diabetes.…”

Targeted siRNA delivery to diseased microvascular endothelial cells—Cellular and molecular concepts

“…However, most of the drugs lack specificity for the endothelium, giving rise to adverse effects in other cells in the body. Formulation of highly potent drugs in EC specific delivery devices will be essential to provide these drugs with a potential for future clinical application (9,11). Critical for success of these approaches is the identification of target epitopes on the diseased endothelial cells as well as choosing the proper drug target and concurrent molecular entity for therapeutic effects.…”

“…A variety of pharmacological approaches to counteract endothelial activation are already applied in the clinic, tested in clinical trials, or in preclinical development, including the potent inhibitors that affect receptor tyrosine kinase activation as well as specific kinases involved in the various signal transduction cascades (9). Besides kinase inhibitors, drugs based on RNA interference (RNAi), i.c., small interfering RNAs (siRNAs), offer increased specificity and efficient gene silencing of diseaseassociated genes.…”

HMG-CoA Reductase Inhibitors and Renal Function

“…Both LDL and ox-LDL induce the expression of NF-B, which has been associated with inflammation in glomerulonephritis and the progression of chronic kidney disease (CKD) (3). It has also been found to induce the expression of genes that encode other cytokines, chemokines, interferons, growth factors, cell adhesion molecules, and MHC proteins involved in inflammation and proliferation (4).…”