Arterial wall-determined risk factors to vascular diseases

Many decades of research have led to considerable in-depth understanding of circulating factors that may lead to coronary atherosclerosis. However, not every individual with serious known risk factors such as hypercholesterolemia or cigarette smoking develops atherosclerosis. Differential susceptibility of the arterial wall to circulating atherogenic risk factors, which may be largely controlled by genetic variants, may provide this missing link. Endothelial cells, the lining of the arterial wall, are responsible for the integrity and responses to the circulating environment. Dysfunctional endothelial cells and the subsequent proliferation of vascular smooth muscle cells are the prelude of atherosclerosis and acute coronary syndrome. Yet, there have been no detailed studies exploring the interaction between circulating environmental and arterial wall endogenous risk factors in living human subjects. This deficiency is largely the result of restricted access. Genetic factors almost certainly play a key role in directing how the arterial wall responds to circulating "environmental" factors. This endogenous-exogenous (i.e. the arterial wall-circulating) blood balance is the reflection of nature-nurture or gene-environment interaction. Understanding the interaction fully will require direct access to the arteries, and nonhuman primates can provide an excellent model for such investigations. In the current review, we discuss the importance of arterial wall factors in vascular diseases and present a baboon model for practical studies of arterial wall factors and their interaction with circulating factors. Direct biopsy access to baboon arteries will provide a unique opportunity to explore arterial wall susceptibilities and to evaluate the direct effects of diet or pharmaceutical agents on vascular diseases. The use of baboons from large pedigreed families in these studies will enable the identification of genes that interact with these environmental factors in determining individual risk of atherosclerosis.     

Coronary atherosclerosis and somatic mutations: an overview of the contributive factors for oxidative DNA damage

Coronary artery disease (CAD) is a multifactorial process that appears to be caused by the interaction of environmental risk factors with multiple predisposing genes. Genetic research on CAD has traditionally focused on investigation aimed at identifying disease-susceptibility genes. Recent evidence suggests that somatically acquired DNA mutations may also contribute significantly to the pathogenesis of the disease, underlining the similarity between atherosclerotic and carcinogenic processes. The generation of oxidative stress has been emphasized as an important cause of DNA damage in atherosclerosis. This review highlights some of the major atherogenic risk factors as likely mediators in the oxidative modification of DNA. It also examines the hypothesis that an increase in oxidative stress may derive from "oxidatively" damaged mitochondria. Accordingly, further research in this field should be given high priority, since increased somatic DNA damage could be an important pathogenic factor and an additional prognostic predictor, as well as a potential target for therapeutic strategies in coronary artery disease.     

Preliminary observations, at the ultrastructural level, on the reactivity of cerebral arteries from New Zealand rabbits to combined atherogenic stimuli (hypercholesterol diet and hypertension)

Both in monkeys (Rhesus and Cynomolgus) and in New Zealand rabbits fed an atherogenic diet, a marked delay in the appearance of atherosclerotic lesions of the cerebral arteries in comparison with other arterial districts has been observed. This appearance has been described in monkeys as relatively earlier if hypertension is added to the atherogenic diet. Preliminary observations on a little group of rabbits on a 3 months hypercholesterolic diet, subjected to Goldblatt aortic coarctation, have shown an increase of blood pressure and a severe gross atherosclerotic involvement of aorta, resembling the one obtainable after 6 months of atherogenic diet. Histologically, the aorta predominantly shows lesions of the fatty streaks type with necrotic areas in the deep; the carotid lesions show some lipid in smooth muscle cells disseminated in a sub-endothelial "edematous" space (rich in protein). The cerebral arteries do not show any lesion. At TEM, the aortic lesions look sometimes as advanced plaques with an initial fibrosis at the surface; the carotid lesions are characterized by a granular deposit in the sub-endothelial space in which some smooth muscle cells (with lipid in the cytoplasm) are present; in the cerebral arteries only the presence of collagen fibers among the smooth muscle cells of the media, never observed in the animals fed the atherogenic diet alone, has sometimes been noted.     

Anti-inflammatory and anti-atherogenic properties of adiponectin

Obesity-related disorders, such as insulin resistance, hypertension and atherosclerosis, are associated with chronic inflammation. Adiponectin is an adipocyte-derived secreted factor that is down-regulated in obese states. Adiponectin exerts the protective actions on obesity-linked diseases, such as insulin resistance and atherosclerosis by attenuating chronic inflammation in its target organs. Adiponectin also exerts the salutary effects on vascular disorders by directly acting on vascular component cells including endothelial cells, smooth muscle cells and macrophages. This review will focus on the role of adiponectin in control of inflammatory responses and atherogenic processes.     

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC Working Paper 7/1/2. Shared risk factors for cancer and atherosclerosis--a review of the epidemiological evidence

This paper reviews the epidemiological literature of relevance for the hypothesis that somatic mutation is involved in the formation of the atherosclerotic plaque. Assuming that somatic mutations are involved in atherogenesis, one would expect at least some of the risk factors for cancer and for atherosclerosis to be identical. Therefore, the review covers the correlated occurrence of cancer and atherosclerotic disease. Special interest is given to populations at high risk of cancer, including subpopulations with certain genetic diseases, and populations exposed to certain carcinogenic environmental agents including ionizing radiation, vinyl chloride monomer (VCM), arsenic, tobacco, and various industrial combustion effluents containing polycyclic aromatic hydrocarbons (PAHs). Exposure to combustion effluents from burning of tobacco or fuel is associated with an increased risk of cancer and atherosclerotic disease. Combustion effluents constitute a complex mixture of potentially hazardous agents, however, and the observed correlation of cancer and atherosclerosis among exposed persons cannot be unambiguously interpreted as evidence of a common etiology of the two groups of diseases. For ionizing radiation, arsenic, and VCM there is suggestive evidence that these agents possess an atherogenic effect beside their well-known carcinogenic properties. Both arsenic and VCM seem to have a specific affinity to the vascular bed causing various lesions including angiosarcomas and atherosclerotic plaques. Regarding ionizing radiation, the atherogenic effects seem to be localized to heavily irradiated fields. Beside the carcinogenic and atherogenic effects, exposure to arsenic, VCM, and ionizing radiation brings about an increase in the incidence of mutations and chromosomal aberrations. A theory involving somatic mutation in the pathogenesis of the atherosclerotic plaque could be consistent with the observed biological effects of ionizing radiation, arsenic, and VCM. The scant data from families with certain inherited diseases may also be consistent with an involvement of the genome in the pathogenesis of atherosclerosis. In conclusion, there is strong epidemiological evidence that several factors associated with an increased risk of cancer are also associated with an increased risk of atherosclerosis.     

Effect of trifluoperazine on cholesterol metabolism of smooth muscle cells exposed to hypercholesterolemic medium in vitro

We recently demonstrated that the preventive effect of trifluoperazine (a potent inhibitor of calmodulin, protein kinase C, and phospholipase A2) on cholesterol-induced atherogenic activity of smooth muscle cells was mediated through its ability to inhibit smooth muscle cellular DNA synthesis coupled with stimulation of LDL receptor synthesis. The present study addressed the effect of trifluoperazine on cholesterol metabolism of aortic SMCs enriched with cholesterol through the nonreceptor pathway and revealed that (a) TFP caused inhibition of cholesterol synthesis compared with control cells bathed with hypercholesterolemic medium alone. (b) The drug also caused inhibition of free cholesterol and cholesteryl ester accumulation within smooth muscle cells compared to control cells. These results demonstrate that the preventive effect of TFP on atherogenic activity of smooth muscle cells may also be due to its ability to affect the altered/modified cholesterol metabolism of smooth muscle cells exposed to hypercholesterolemic medium in vitro.     

Cardiovascular risk factors, erection disorders and endothelium dysfunction

Upon sexual stimulation, penile erection, occurring in response to the activation of pro-erectile autonomic pathways, is greatly dependent on adequate inflow of blood to the erectile tissue and requires coordinated arterial endothelium-dependent vasodilatation and sinusoidal endothelium-dependent corporal smooth muscle relaxation. Nitric oxide (NO) is the principal peripheral pro-erectile neurotransmitter which is released by both non-adrenergic, non-cholinergic neurons and the sinusoidal endothelium to relax corporal smooth muscle through the cGMP pathway. Any factors modifying the basal corporal tone, the arterial inflow of blood to the corpora, the synthesis/release of neurogenic or endothelial NO are prime suspects for being involved in the pathophysiology of erectile dysfunction (ED). In fact, conditions associated with altered endothelial function, such as ageing, hypertension, hypercholesterolemia and diabetes, may, by changing the balance between contractant and relaxant factors, cause circulatory and structural changes in penile tissues, resulting in arterial insufficiency and defect in smooth muscle relaxation and thus, ED. There is increasing evidence to suggest that ED is predominantly a vascular disease and may even be a marker for occult cardiovascular disease. Recent results illustrating the importance of endothelial dysfunction in the pathophysiology of different forms of experimental ED are discussed. These pathways may represent new potential treatment targets.     

Role of the arterial smooth muscle cell in the pathogenesis of atherosclerosis

The development of an atherosclerotic lesion is characterised by a proliferation of arterial smooth muscle cells and an accumulation of cholesterol, cholesteryl esters and connective tissue. The main connective tissue components of an atherosclerotic lesion, i.e. acidic glycosaminoglycans and collagen, are synthesized by the smooth muscle cells. Cholesterol is chiefly derived from plasma lipoproteins, but there is an enhanced intracellular esterification of cholesterol in the cells of the lesions. The important role of the arterial smooth muscle cell in the development of atherosclerotic lesions has resulted in cultures of these cells being used as experimental models to study the pathogenesis of atherosclerosis. Such studies have revealed many blood-derived and other substances affecting proliferation, as well as lipid and connective tissue metabolism of arterial smooth muscle cells. In this way certain risk factors for cardiovascular disease have turned out to be associated with the metabolic disturbances of atherogenesis at the cellular level. Studies with cultured arterial smooth muscle cells have also demonstrated other factors for example one derived from aggregating platelets that may significantly contribute to the development of atherosclerotic lesions. On the other hand, certain inherent features of the smooth muscle cells of the lesions, such as enhanced proliferation and synthesis of glycosaminoglycans, may also contribute to the pathological changes.     

Platelet factors stimulate fibroblasts and smooth muscle cells quiescent in plasma serum to proliferate

Whole blood serum is widely recognized as essential for the growth of diploid cells in culture. Dermal fibroblasts and arterial smooth muscle cells fail to proliferate in culture in the presence of serum derived from platelet-poor plasma. Platelet-poor plasma serum is capable of maintaining monkey arterial smooth muscle cells quiescent in culture at either low (1.5 x 10(3)) or high (2.0 x 10(4)) population densities. The proportion of cell traversing the cell cycle under these conditions was approximately 3%. Equal numbers of quiescent smooth muscle cells initiated DNA synthesis and cell division when treated with whole blood serum or with an equivalent quantity of platelet-poor plasma serum supplemented with a factor(s) derived from a supernate obtained after exposure of human platelets to purified thrombin in vitro.     

Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis

Chronic inflammation of gastrointestinal tissues is a well-recognized risk factor for the development of epithelial cell-derived malignancies. Although the inflammatory mediators linking chronic inflammation to carcinogenesis are numerous, current information suggests that nitric oxide (NO) contributes to carcinogenesis during chronic inflammation. Inducible nitric oxide synthase (iNOS), expressed by both macrophages and epithelial cells during inflammation, generates the bioreactive molecule NO. In addition to causing DNA lesions, NO can directly interact with proteins by nitrosylation and nitosation reactions. The consequences of protein damage by NO appear to be procarcinogenic. For example, NO inhibits DNA repair enzymes such as human 8-oxodeoxyguanosine DNA glycosylase 1 and blocks apoptosis via nitrosylation of caspases. These cellular events permit DNA damage to accumulate, which is required for the numerous mutations necessary for development of invasive cancer. NO also promotes cancer progression by functioning as an angiogenesis factor. Strategies to inhibit NO generation during chronic inflammation or to scavenge reactive nitrogen species may prove useful in decreasing the risk of cancer development in chronic inflammatory gastrointestinal diseases.     

Vitamin D deficiency in children with cerebral palsy: A narrative review of epidemiology,contributing factors,clinical consequences and interventions

Sufficient vitamin D levels are necessary, not only for mineralization, normal growth and development of bones, but also for the prevention of fatal chronic diseases like diabetes mellitus, metabolic syndrome and cancer. This is of particular importance in children with neuro- and musculoskeletal disorders, especially cerebral palsy (CP). CP is a heterogeneous group of childhood developmental disability disorders described by uncharacteristic posture, balance, and movement. Patients with CP are at an increased risk of vitamin D deficiency and as a result reduced bone mineral density, bone fragility, osteopenia, and rickets. The present review aims to combine and summarize available evidence, regarding the epidemiology, underlying contributing factors, clinical consequences, and treatment interventions of vitamin D deficiency in children with CP.     

Role of proteomic technologies in understanding risk of arterial thrombosis

Arterial thrombosis is a pivotal event in the development of cardiovascular diseases. Plasma and cellular proteins have the potential to influence thrombus morphology and function. This review summarizes the latest studies to use proteomic technologies to characterize the cellular and plasma components involved in arterial thrombosis, with a view to understanding the pathogenesis and treatment of acute cardiovascular diseases. Proteomic approaches have been extensively used to profile the proteome of endothelial cells, leukocytes, vascular smooth muscle cells, platelets and plasma in the search for risk factors for cardiovascular disease; however, further work is required to validate the direct contribution of these proteins to arterial thrombosis.     

Vascular smooth muscle cell senescence and age-related diseases: State of the art

Aging is a worldwide challenge, and it is accompanied by the accumulation of senescent cells. Cellular senescence is traditionally defined as permanent cell growth arrest and currently includes the senescence-associated secretory phenotype (SASP). There are two main types of cellular senescence, including telomere-dependent replicative senescence and stress-induced premature senescence. The process of cellular senescence is mainly controlled by two effector pathways, namely, the p53-p21 and p16-retinoblastoma protein (pRB) pathways. Vascular smooth muscle cells (VSMCs) are integral parts of arteries and play an important role in vascular structure and function. VSMC senescence may be triggered by many factors, such as angiotensin II, oxidative stress, inflammation, DNA damage, and small molecule compounds. These inducers are able to genetically and epigenetically regulate VSMC senescence. The senescence of VSMCs together with the SASP contributes to chronic vascular inflammation, the loss of arterial function, and the development of age-related diseases. Current evidence suggests that the senescence of VSMCs might be harmful to individual health, whereas its influence on the lifespan is not clear. The purpose of this paper was to review the current knowledge regarding VSMC senescence and its relevance to hypertension, atherosclerosis, and diabetes, as well as the potential mechanisms responsible for VSMC senescence in these age-related diseases.     

Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis

Infection and chronic inflammation are proposed to contribute to carcinogenesis through inflammation-related mechanisms. Infection with hepatitis C virus, Helicobacter pylori and the liver fluke, Opisthorchis viverrini (OV), are important risk factors for hepatocellular carcinoma (HCC), gastric cancer and cholangiocarcinoma, respectively. Inflammatory bowel diseases (IBDs) and oral diseases, such as oral lichen planus (OLP) and leukoplakia, are associated with colon carcinogenesis and oral squamous cell carcinoma (OSCC), respectively. We performed a double immunofluorescence labeling study and found that nitrative and oxidative DNA lesion products, 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), were formed and inducible nitric oxide synthase (iNOS) was expressed in epithelial cells and inflammatory cells at the site of carcinogenesis in humans and animal models. Antibacterial, antiviral and antiparasitic drugs dramatically diminished the formation of these DNA lesion markers and iNOS expression. These results suggest that oxidative and nitrative DNA damage occurs at the sites of carcinogenesis, regardless of etiology. Therefore, it is considered that excessive amounts of reactive nitrogen species produced via iNOS during chronic inflammation may play a key role in carcinogenesis by causing DNA damage. On the basis of our results, we propose that 8-nitroguanine is a promising biomarker to evaluate the potential risk of inflammation-mediated carcinogenesis.     

Biomarker responses in human populations: towards a worldwide map.

The discipline of epidemiology studies the determinants of diseases in human populations, identifies causes, determines outcomes and develops prevention strategies. Traditional epidemiology is most useful for studies of acute, relatively common diseases with short incubation periods but less so for studies of chronic low incidence diseases with long incubation periods. Molecular epidemiology, which employs biological responses or biomarkers as surrogates of exposures or effects, can help with the latter. For this reason, there is a great interest in developing and validating biomarkers. DNA damage underlies an important group of chronic diseases with long incubation periods, i.e., cancer. Biomarkers may measure the exposures that induce the DNA damage, the damage itself, or individual susceptibility to damage. Before they can be used for human population research, however, these measures must be validated. Biomarker validation critically depends on field studies. This is accomplished through transitional epidemiological studies that 'bridge the gap' between laboratory and field. Transitional epidemiological studies are of three varieties: (i) Developmental, (ii) Characterization, and (iii) Applied. Biomarkers are the dependent variables in transitional studies. An international network of laboratories for human population monitoring requires yet another dimension for validation, i.e., the comparability of results among laboratories must be determined. This will be achieved by sample sharing projects, with workshops to compare results. Only then can results in one population be compared with results in another. Interlaboratory standardization of assays for biomarkers validated by transitional studies will have far-reaching benefits. It will allow development of worldwide databases of background values for the various biomarkers-or biomarker maps. This, in turn, will facilitate problem identification and eventually constitute the baselines for area-specific population monitoring. Biomarker databases so developed can be compared with worldwide databases for cancer and heritable diseases, validating the former as statistical surrogates of the latter.     

Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress

Hepatocellular cancer is the fifth most frequent cancer in men and the eighth in women worldwide. Established risk factors are chronic hepatitis B and C infection, chronic heavy alcohol consumption, obesity and type 2 diabetes, tobacco use, use of oral contraceptives, and aflatoxin-contaminated food. Almost 90% of all hepatocellular carcinomas develop in cirrhotic livers. In Western countries, attributable risks are highest for cirrhosis due to chronic alcohol abuse and viral hepatitis B and C infection. Among those with alcoholic cirrhosis, the annual incidence of hepatocellular cancer is 1-2%. An important mechanism implicated in alcohol-related hepatocarcinogenesis is oxidative stress from alcohol metabolism, inflammation, and increased iron storage. Ethanol-induced cytochrome P-450 2E1 produces various reactive oxygen species, leading to the formation of lipid peroxides such as 4-hydroxy-nonenal. Furthermore, alcohol impairs the antioxidant defense system, resulting in mitochondrial damage and apoptosis. Chronic alcohol exposure elicits hepatocyte hyperregeneration due to the activation of survival factors and interference with retinoid metabolism. Direct DNA damage results from acetaldehyde, which can bind to DNA, inhibit DNA repair systems, and lead to the formation of carcinogenic exocyclic DNA etheno adducts. Finally, chronic alcohol abuse interferes with methyl group transfer and may thereby alter gene expression.     

Inflammation,oxidative stress,and cardiovascular disease risk factors in adults with cystic fibrosis

Cystic fibrosis (CF) represents one of a number of localized lung and non-lung diseases with an intense chronic inflammatory component associated with evidence of systemic oxidative stress. Many of these chronic inflammatory diseases are accompanied by an array of atherosclerotic processes and cardiovascular disease (CVD), another condition strongly related to inflammation and oxidative stress. As a consequence of a dramatic increase in long-lived patients with CF in recent decades, the specter of CVD must be considered in these patients who are now reaching middle age and beyond. Buttressed by recent data documenting that CF patients exhibit evidence of endothelial dysfunction, a recognized precursor of atherosclerosis and CVD, the spectrum of risk factors for CVD in CF is reviewed here. Epidemiological data further characterizing the presence and extent of atherogenic processes in CF patients would seem important to obtain. Such studies should further inform and offer mechanistic insights into how other chronic inflammatory diseases potentiate the processes leading to CVDs.     

Increased resistance to oxidative DNA damage of trabecular meshwork cells by E. coli FPG gene transfection

Oxidative damage plays a pathogenic role in various chronic degenerative diseases. Oxidative damage targeting trabecular meshwork (TM) cells as a consequence of mitochondrial damage is a pathogenic mechanism for glaucoma, the most common cause of irreversible blindness worldwide. Consequences of oxidative damage are attenuated by endocellular activities involved in scavenging reactive oxidative species and DNA repair. Selected bacterial genes are highly efficient at protecting cells from oxidative DNA damage. This situation occurs for Escherichia coli formamidopyrimidine DNA glycosylase (FPG), a major DNA glycosylase that repairs oxidatively damaged DNA. Accordingly, this study was aimed at transfecting human TM cells (HTMC) with Fpg in order to increase their resistance to oxidative damage. This study demonstrates that it is feasible to increase resistance of HTMC to endogenous oxidative damage by gene transfection. These findings bear relevance for primary and secondary prevention of degenerative glaucomas and other degenerative diseases where oxidative damage plays a pathogenic role.