Publisher Summary This chapter discusses the role of free radicals and catalytic metal ions in human disease. The importance of transition metal ions in mediating oxidant damage naturally leads to the question as to what forms of such ions might be available to catalyze radical reactions in vivo . The chapter discusses the metabolism of transition metals, such as iron and copper. It also discusses the chelation therapy that is an approach to site-specific antioxidant protection. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. A wide range of techniques is available to measure the rate of this process, but none is applicable to all circumstances. The two most popular are the measurement of diene conjugation and the thiobarbituric acid (TBA) test, but they are both subject to pitfalls, especially when applied to human samples. The chapter also discusses the essential principles of the peroxidation process. When discussing lipid peroxidation, it is essential to use clear terminology for the sequence of events involved; an imprecise use of terms such as initiation has caused considerable confusion in the literature. In a completely peroxide-free lipid system, first chain initiation of a peroxidation sequence in a membrane or polyunsaturated fatty acid refers to the attack of any species that has sufficient reactivity to abstract a hydrogen atom from a methylene group.

Role of free radicals and catalytic metal ions in human disease: an overview.

Diabetes mellitus is commonly associated with systolic/diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive control subjects, a heightened plasma insulin response to a glucose challenge is consistently found. A state of cellular resistance to insulin action subtends the observed hyperinsulinism. With the insulin/glucose-clamp technique, in combination with tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (muscle), is limited to nonoxidative pathways of glucose disposal (glycogen synthesis), and correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: Na+ retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth muscle cells. Physiological maneuvers, such as calorie restriction (in the overweight patient) and regular physical exercise, can improve tissue sensitivity to insulin; evidence indicates that these maneuvers can also lower blood pressure in both normotensive and hypertensive individuals. Insulin resistance and hyperinsulinemia are also associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate-density and low-density lipoproteins, both of which are atherogenic. Last, insulin, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of various growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including non-insulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.

Insulin Resistance: A Multifaceted Syndrome Responsible for NIDDM, Obesity, Hypertension, Dyslipidemia, and Atherosclerotic Cardiovascular Disease

Vascular calcification is a common finding in atherosclerosis and a serious problem in diabetic and uremic patients. Because of the correlation of hyperphosphatemia and vascular calcification, the ability of extracellular inorganic phosphate levels to regulate human aortic smooth muscle cell (HSMC) culture mineralization in vitro was examined. HSMCs cultured in media containing normal physiological levels of inorganic phosphate (1.4 mmol/L) did not mineralize. In contrast, HSMCs cultured in media containing phosphate levels comparable to those seen in hyperphosphatemic individuals (>1.4 mmol/L) showed dose-dependent increases in mineral deposition. Mechanistic studies revealed that elevated phosphate treatment of HSMCs also enhanced the expression of the osteoblastic differentiation markers osteocalcin and Cbfa-1. The effects of elevated phosphate on HSMCs were mediated by a sodium-dependent phosphate cotransporter (NPC), as indicated by the ability of the specific NPC inhibitor phosphonoformic acid, to dose dependently inhibit phosphate-induced calcium deposition as well as osteocalcin and Cbfa-1 gene expression. With the use of polymerase chain reaction and Northern blot analyses, the NPC in HSMCs was identified as Pit-1 (Glvr-1), a member of the novel type III NPCs. These data suggest that elevated phosphate may directly stimulate HSMCs to undergo phenotypic changes that predispose to calcification and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. The full text of this article is available at http://www.circresaha.org.

Phosphate regulation of vascular smooth muscle cell calcification.

Background Although MRI can discriminate the lipid core from the collagenous cap of atherosclerotic lesions in vitro with T2 contrast, it has not yet produced detailed in vivo images of these human plaque components Methods and Results We imaged seven lesions from six patients who required surgical carotid endarterectomy and calculated T2 in vivo before surgery in various plaque regions Using the same acquisition parameters, we repeated these measurements in vitro on the resected fragment and compared MR images with histology T2 values calculated in vivo correlate with in vitro measurements for each plaque component; the in vitro discrimination we demonstrated previously with T2 contrast can therefore be performed similarly in vivo Conclusions MRI is the first noninvasive imaging technique that allows the discrimination of lipid cores, fibrous caps, calcifications, normal media, and adventitia in human atheromatous plaques in vivo This technique also characterizes intraplaque hemorrhage and acute thr

Magnetic resonance images lipid, fibrous, calcified, hemorrhagic, and thrombotic components of human atherosclerosis in vivo.

In an earlier report, we used differential cloning to identify genes that might be critical in controlling arterial neointima formation (Giachelli, C., N. Bae, D. Lombardi, M. Majesky, and S. Schwartz. 1991. Biochem. Biophys. Res. Commun. 177:867-873). In this study, we sequenced the complete cDNA and conclusively identified one of these genes, 2B7, as rat osteopontin. Using immunochemistry and in situ hybridization, we found that medial smooth muscle cells (SMC) in uninjured arteries contained very low levels of osteopontin protein and mRNA. Injury to either the adult rat aorta or carotid artery using a balloon catheter initiated a qualitatively similar time-dependent increase in both osteopontin protein and mRNA in arterial SMC. Expression was transient and highly localized to neointimal SMC during the proliferative and migratory phases of arterial injury, suggesting a possible role for osteopontin in these processes. In vitro, basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-beta), and angiotensin II (AII), all proteins implicated in the rat arterial injury response, elevated osteopontin expression in confluent vascular SMC. Finally, we found that osteopontin was a novel component of the human atherosclerotic plaque found most strikingly associated with calcified deposits. These data implicate osteopontin as a potentially important mediator of arterial neointima formation as well as dystrophic calcification that often accompanies this process.

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Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques

In vascular smooth muscle (as in myocardial fibers), a transmembrane supply of calcium ions is required for active tension development. In consequence, calcium antagonists possess a wide scope of action against practically all types of vasoconstrictor or spastic responses of arterial smooth muscle cells. Calcium antagonists are the drugs of choice for the treatment of coronary, pulmonary, cerebral or mesenteric artery spasms. Other clinically important targets of calcium antagonists are the systemic resistance vessels that rapidly dilate, which explains why calcium antagonists are increasingly used for the treatment of acute hypertensive crises as well as for antihypertensive long-term therapy. In physiologic experiments, calcium antagonists normalize the blood pressure of spontaneously hypertensive rats, neutralize various vasoconstrictor agents (if they act via promotion of transmembrane calcium influx), and greatly reduce the sensitivity of the systemic arteries and arterioles to mechanical stimuli, which can produce additional vasoconstriction, if a rise in intraluminal pressure stretches the vascular wall (Bayliss effect). Calcium antagonists also prevent noxious arterial calcium overload in animals. In the human arterial walls, at an advanced age, pathogenic degrees of calcium accumulation are reached and probably play an important role in both the development of hypertension and of arteriosclerotic lesions. Hypertensive rats exhibit progressive arterial calcium overload that responds well to the calcium antagonists nifedipine, nimodipine, nisoldipine and nitrendipine, as well as to verapamil.

Antihypertensive and arterial anticalcinotic effects of calcium antagonists

The role of calcium in the pathogenesis of experimental arteriosclerosis

Heart muscle fibres always undergo severe functional and structural alterations, finally resulting in necrotization, if free extracellular Ca2+ ions penetrate abundantly through the sarcolemma membrane into the myoplasm, so that the capacities of the Ca2+ binding or extrusion processes become overpowered. The crucial reaction consists of high-energy phosphate exhaustion which is brought about (a) by excessive activation of Ca2+-dependent intracellular ATPases, and (b) by Ca2+ induced impairment of the mitochondria. Intracellular Ca2+ overload proved to the common denominator in the pathogenesis of severe myocardial fibre injury and death produced under the following circumstances: Overdoses of β-adrenergic catecholamines, dihydrotachysterol or vitamin D3 alimentary K+ or Mg2+ deficiency, hereditary cardiomyopathy of Syrian hamsters. Moreover, intracellular Ca2+ overload develops in the course of myocardial hypoxia or ischaemia thus causing additional precipitous damage of the mitochrondria. Following our first observations made in 1968, it has turned out that in all these cases, Ca2+ antagonists are capable of protecting myocardial cell integrity in that they prevent excessive transmembrane Ca2+ uptake. This is also true of the Ca2+ paradox: Ca2+ antagonists possibly inhibit the development of sarcolemmal leaks in the Ca2+ deprived myocardium. However, it is more likely that Ca2+ antagonists restrict the exaggerated influx of Ca2+ through these leaks, when the Ca2+ myocardial fibres return to a normal Ca2+ medium.

Consequences of uncontrolled calcium entry and its prevention with calcium antagonists

In vascular smooth muscle (as in myocardial fibers) a transmembrane supply of Ca ++ ions is required for active tension development. In consequence, Ca ++ antagonists, which restrict transmembrane Ca ++ delivery, possess a wide scope of action against practically all types of vasoconstrictor or spastic reactions on coronary, pulmonary, cerebral, renal or mesenteric arteries. Another important target of Ca ++ antagonists is the resistance vessels of systemic circulation in both animals and humans. Thus, Ca ++ antagonists are successfully used for the treatment of acute hypertensive crises as well as for long-term antihypertensive therapy. Spontaneously hypertensive rats (SHRs) also respond to suitable Ca ++ antagonists with a dramatic fall in blood pressure. The acute spasmolytic effects of Ca ++ antagonists can be directly visualized by ophthalmoscopic examination of the arterioles in the ocular fundus. In untreated SHRs these arterioles are always heavily constricted, and aneurysm-like luminal protuberances develop. In contrast, after 1 adequate Ca ++ antagonist dose, blood pressure instantaneously falls to its normal level white the retinal arterioles dilate. A further important effect of Ca ++ antagonists that we have demonstrated in experiments on SHRs is the prevention of progressive arterial Ca ++ overload, which otherwise produces severe calcinotic or arteriosclerotic damage of the arterial walls. However, with the help of Ca ++ antagonists, arterial integrity can be totally preserved. Interestingly, this anticalcinotic arterial protection by Ca ++ antagonists may also manifest itself independent of any blood pressure change. This is true of arterial calcinosis in normotensive rats because of advanced age, alloxan diabetes or intoxication with overdoses of vitamin D 3 , dihydrotachysterol or nicotine.

Experimental basis of the long-term therapy of arterial hypertension with calcium antagonists

There are several reasons to expect that the use of calcium antagonists to treat cardiovascular disease will continue to spread. The scope of indications for existing calcium antagonists is expanding; new calcium antagonists with more selective organ affinity are being developed and these drugs may be given over the long term for prophylaxis against hypertension and for vasoprotection. In all probability, the long-term prophylactic use of calcium antagonists offers the most promise. The long-term effects of calcium antagonists for treating hypertension as well as for preventing vascular damage due to calcinosis and sclerosis will be discussed.

Future directions in the use of calcium antagonists

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