Demystifying the ACE polymorphism: from genetics to biology.

The angiotensin converting enzyme (ACE) I/D polymorphism has been one of the most studied genetic systems. It comprises hundreds of reports and a myriad of disease associations, including cardiovascular, metabolic, immune, cancer, aging, neurodegenerative and psychiatric diseases. Despite the wealth of information on the ACE polymorphism and the well-known functions of ACE, several questions arise.

Oleuropein, a non-toxic olive iridoid, is an anti-tumor agent and cytoskeleton disruptor.

Oleuropein, a non-toxic secoiridoid derived from the olive tree, is a powerful antioxidant and anti-angiogenic agent. Here, we show it to be a potent anti-cancer compound, directly disrupting actin filaments in cells and in a cell-free assay. Oleuropein inhibited the proliferation and migration of advanced-grade tumor cell lines in a dose-responsive manner.

Involvement of protein kinase CK2 in angiogenesis and retinal neovascularization.

Purpose: The purpose of the study was to characterize signaling intermediates involved in angiogenic responses of retinal endothelial cells (RECs) to the extracellular matrix and growth factors, by using specific inhibitors.

Methods: Tubelike structure formation and the development of secondary sprouts on a basement membrane (BM) matrix, cell proliferation, and cell migration were studied in cultures of bovine and human RECs. Specific inhibitors were tested for inhibition of retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR).

A genetic variant of ACE increases cell survival: a new paradigm for biology and disease.

The human angiotensin converting enzyme (ACE) polymorphism is caused by an Alu element insertion resulting in three genotypes (Alu+/+, Alu+/-, Alu-/-, or ACE-II, ACE-ID, and ACE-DD, respectively), with ACE-II displaying lower ACE activity. The polymorphism is associated with athletic performance, aging, and disease. Population studies, however, were confounding because variants of the polymorphism appeared to fortuitously correlate with health and various pathological states.

ACE inhibition actively promotes cell survival by altering gene expression.

We tested the effect of ACE inhibition on the survival of bovine retinal (REC) and choroidal (CEC) endothelial cells (EC) in culture. The ACE inhibitor captopril delayed the apoptotic tube collapse of REC on Matrigel for >15 days. Captopril treatment of confluent monolayers (2-8 weeks) followed by slow starvation (2-4 weeks) increased EC viability by approximately 200%.

Oxysterol-induced toxicity in R28 and ARPE-19 cells.

Studies have shown an intimate relationship between cholesterol and retinal diseases; we examined the effects of cholesterol oxides on cultured cells. Using the rat retinal precursor cell line R28 and the human RPE cell line ARPE-19, we investigated the potential cytotoxicity of cholesterol oxides. Cultured R28 and ARPE-19 cells were treated with either 25-hydroxycholesterol and 7-ketocholesterol (0-50 microg/ml).

Nerve growth factor regulates neuroectodermal tumor cell responses to mitogenic growth factors.

Previous studies showed that nerve growth factor (NGF) decreases the proliferation of neuroectodermal tumor (NET) cells (C-1300 and Neuro2A murine neuroblastoma, PC12 rat pheochromocytoma) within 5-7 days in a dose-dependent manner. This effect is regulated by the concentration of serum in the culture medium. Therefore, we hypothesized that NGF exerts its antimitogenic activities by interfering with the proliferative action of other growth factors.

Effects of tenascin-C on normal and diabetic retinal endothelial cells in culture.

Purpose: Tenascin-C (TN-C) is expressed in embryogenesis, tissue remodeling, and healing. It is up-regulated in retinas of patients affected by diabetic retinopathy (DR). Because TN-C may promote neovascularization, its potential angiogenic effects were examined in vitro in normal and diabetic retinal endothelial cells (RECs).

Alu DNA polymorphism in ACE gene is protective for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. We report an association between an Alu polymorphism in the angiotensin-converting enzyme (ACE) gene with the dry/atrophic form of AMD. Using the polymerase chain reaction (PCR) on genomic DNA isolated from patients with AMD (n=173), and an age-matched control population (n=189), we amplified a region polymorphic for an Alu element insertion in the ACE gene.

Effects of angiogenic growth factor combinations on retinal endothelial cells.

The aim of this paper was to determine if growth factors, known to be upregulated in proliferative diabetic retinopathy, exerted combined effects on retinal endothelial cells. The authors explored the individual and collective actions of insulin-like growth factor I (IGF-I), vascular endothelial growth factor (VEGF), platelet-derived growth factor-BB (PDGF-BB), fibroblast growth factor-2 (FGF-2) and placenta growth factor (PlGF) on several parameters that reflect the angiogenic potential of endothelial cells. The effect of growth factors on cell migration and survival/proliferation was examined using primary cultures of bovine retinal endothelial cells (BREC).