Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

The role of angiotensin II in regulating vascular structural and functional changes in hypertension

A major hemodynamic abnormality in hypertension is increased peripheral resistance due to changes in vascular structure and function. Structural changes include reduced lumen diameter and arterial wall thickening. Functional changes include increased vasoconstriction and/or decreased vasodilation. These processes are influenced by many humoral factors, of which angiotensin II (Ang II) seems to be critical. At the cellular level, Ang II stimulates vascular smooth muscle cell growth, increases collagen deposition, induces inflammation, increases contractility, and decreases dilation. Molecular mechanisms associated with these changes in hypertension include upregulation of many signaling pathways, including tyrosine kinases, mitogen-activated protein kinases, RhoA/Rho kinase, and increased generation of reactive oxygen species. This review focuses on the role of Ang II in vascular functional and structural changes of small arteries in hypertension. In addition, cellular processes whereby Ang II influences vessels in hypertension are discussed. Finally, novel concepts related to signaling pathways by which Ang II regulates vascular smooth muscle cells in hypertension are introduced

Hypertensive vasculopathy

Essential hypertension is characterized by an increase in total peripheral vascular resistance, due primarily to a decrease in lumen diameter and an increase in media thickness. Underlying these phenomena are altered vascular tone (decreased relaxation and/or increased contraction) and structural remodeling. Endothelial dysfunction and arterial remodeling characterize the vascular phenotype of hypertension, known as “hypertensive vasculopathy.” Initial factors contributing to vasculopathy of hypertension involve increased transmural pressure, changes in blood flow, impaired endothelial function, and altered vascular smooth muscle cell (VSMC) contractility. More chronic changes are associated with perturbed VSMC growth, migration, differentiation, calcification and inflammation, and production of extracellular matrix proteins, responsible for structural remodeling. At the level of the vascular cells, receptors are activated by vasoactive agents and mechanical forces triggering intracellular signaling pathways and generation of reactive oxygen species (ROS). These subcellular events underlie VSMC dedifferentiation, realignment, calcification, and growth and stimulate inflammation, fibrosis, and osteogenic transformation, which contribute to endothelial dysfunction and thickening of the vascular wall. Such changes play a major role in the vasculopathy of hypertension