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Biomedical subjects

A Faggiotto

Publications and source records attributed to A Faggiotto.

At least 19 recordsLinked to original sources
PubMed2000

Do pleiotropic effects of statins beyond lipid alterations exist in vivo? What are they and how do they differ between statins?

The inhibition of cellular proliferation, the restoration of endothelial activity, the inhibition of platelet reactivity, and an antioxidant potential are only a few examples of pleiotropic effects of statins. This review analyzes the current knowledge on the pleiotropic properties of this class of drugs and examines the relevant data that support the presence of these effects in vivo. The favorable outcome of major trials of statins has indicated that pleiotropic factors indeed play a role in cardiovascular protection. In addition, recent data indicate that many pleiotropic effects influence mechanisms that belong to the extravascular compartment, as well. Perhaps, some of these properties may eventually justify additional indications for statins and improve the treatment of other diseases, including inflammation and cancer.

Anticholesteremic Agents↗
PubMed2000

[The treatment and outlook of atherosclerosis today].

Nowadays, the success of atherosclerosis therapy and the efficacy of cardiovascular disease prevention can rely on a comprehensive strategy. New algorithms derived from large population studies have improved the risk evaluation for the single individual and, consequently, the therapeutic approach can be better adapted to the specific needs of the patient. Improvements of noninvasive techniques, such as B-mode ultrasound and magnetic resonance imaging, allow for the reproducible and precise monitoring of lesion evolution that can be easily applied to large population samples. Ongoing studies regarding the relationship between circulating markers of atherosclerosis and the occurrence of cardiovascular events will improve our assessment of impending risk. Finally, the presence of pleiotropic effects of statins in vivo (and, perhaps, of fibrates as well) underscores the added value of this class of drugs in the treatment of lipid disorders and in the prevention of cardiovascular events. Prospectively, the integration of all these approaches will have a desirable impact on the qualitative improvement of human longevity.

Arteriosclerosis↗
PubMed1999

State-of-the-Art lecture. Statins and blockers of the renin-angiotensin system: vascular protection beyond their primary mode of action.

In addition to their primary mode of action, statins and blockers of the renin-angiotensin system possess common additional properties that are under active investigation. The inhibition of cellular proliferation, the restoration of endothelial activity, the inhibition of platelet reactivity, and an antioxidant potential are only a few examples of shared effects that target the arterial wall. These and other properties may eventually become exploited for the improved treatment of cardiovascular diseases and of other diseases apparently unrelated to the cardiovascular field, including inflammation and cancer. This review analyzes the current knowledge on the pleiotropic properties of these classes of drugs. Direct comparison indicates that study of the associations among these drugs may eventually disclose additive or synergistic effects that, perhaps even at lower dosages, may provide improved vascular protection and a strong alliance against several atherogenic mechanisms.

Animals↗
PubMed1998

Antioxidants and coronary artery disease.

Data on the protective role of antioxidants in models of atherosclerosis are only partially confirmed in man. Observational and epidemiological data, as well as randomized trials, provide no clear cut indications, because of positive and disappointing results on the use of antioxidants in cardiovascular protection. Despite the lack of a general consensus, recent data reinforce the concept that the regular intake of antioxidants present in food limits the progression of atherosclerosis. When it is possible to monitor the efficacy of any antioxidant therapy with validated markers of oxidation, the potential influence of vitamins and antioxidants on coronary artery disease may eventually be resolved.

Adult↗
PubMed1997

Increased J774 macrophage cytotoxicity of late postprandial triglyceride-rich lipoproteins from normolipidemic young men expressing an apolipoprotein epsilon 4 allele.

It has been demonstrated that normolipidemic young men with apolipoprotein E4/3 phenotype have a prolonged postprandial clearance of triglyceride-rich lipoproteins following a high-fat diet. In the present study, we isolated fasting and postprandial (3 and 8 h) lipoprotein fraction from normolipidemic young men with E3/3 and E4/3 phenotypes and examined the in vitro cytotoxicity of these lipoproteins towards J774 macrophages. 8 h E4/3 very low density lipoprotein (VLDL) were significantly more cytotoxic than either 8 h E3/3 VLDL or fasting and 3 h E4/3 VLDL (lactate dehydrogenase (LDH) released: 161 +/- 21, 107 +/- 9, 88 +/- 16 and 101 +/- 12 I.U./l, respectively). Fasting E4/3 intermediate density lipoprotein (IDL) were also significantly more cytotoxic than either fasting E3/3 IDL or 3 h and 8 h E4/3 IDL (LDH released: 105 +/- 23, 60 +/- 9, 37 +/- 5 and 53 +/- 16 I.U./l, respectively), whereas either fasting or postprandial low density lipoprotein (LDL) and high density lipoprotein (HDL) samples did not show any difference in cytotoxicity between the two groups studied. 8 h E4/3 VLDL samples incubated with J774 macrophages had a lower esterified cholesterol (40 +/- 3 versus 52 +/- 3 micrograms), and higher triglyceride (783 +/- 133 versus 418 +/- 64 micrograms) and free fatty acid (FFA) (2.0 +/- 0.4 versus 0.9 +/- 0.1 microgram) content than fasting E4/3 VLDL. The increased macrophage cytotoxicity of late postprandial triglyceride-rich lipoproteins seems to be related to the FFA content of E4/3 VLDL.

Adult↗
PubMed1997

Cerivastatin: pharmacology of a novel synthetic and highly active HMG-CoA reductase inhibitor.

The pyridine derivative cerivastatin is a new entirely synthetic and enantiomerically pure inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. As a sodium salt cerivastatin is present in the active, open ring form. Cerivastatin inhibited the membrane-bound (non-solubilized) HMG-CoA reductase of the native microsomal fraction isolated from rat liver with a Ki value of 1.3 x 10(-9) M. The reference compound lovastatin was 100-fold less potent and exhibited a Ki value of 150 x 10(-9) M. Cerivastatin inhibited the cholesterol synthesis in the human hepatoma cell line HepG2 cells with a similar IC50 value of 1.0 x 10(-9) M. In vivo studies reflected its high in vitro activity. In both rats and dogs, cerivastatin inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate with an oral ED50 value of 0.002 mg/kg body weight, while lovastatin exhibited an oral ED50 value of 0.3 mg/kg in rats, showing again the ratio of 100 or more between cerivastatin and lovastatin. In the small intestine and testes, cerivastatin was at least 50-fold less active with oral ED50 values higher than 0.1 mg/kg, which is indicative for a high liver selectivity of cerivastatin. In cholestyramine-primed dogs cerivastatin dose-dependently lowered the serum cholesterol concentrations by up to 59% with 0.1 mg/kg after 20 days. Interestingly, the serum triglycerides were markedly reduced by 53 and 76% with 0.03 and 0.1 mg/kg, respectively. In normal chow fed dogs the low density lipoprotein (LDL) concentrations were reduced by up to 75% after 0.1 mg cerivastatin/kg. The ratio of HDL/LDL increased by 81% compared with a change of only 14% in the placebo treated control group. The antiatherogenic effect of cerivastatin was shown in rabbits fed a diet enriched with 0.2% cholesterol. After 9 weeks on diet 0.1 mg cerivastatin/kg decreased the accumulation of cholesterol ester in the arterial tissue by 73%. In summary, these data as compared to published data on other HMG-CoA reductase inhibitors demonstrate cerivastatin to be the most active compound in this class. Vastatins used in therapy are effective in mg doses, while cerivastatin offers a new low dose therapy in the microg range.

Administration, Oral↗
PubMed1996

Effect of the new HMG-CoA reductase inhibitor cerivastatin (BAY W 6228)on migration, proliferation and cholesterol synthesis in arterial myocytes.

The major relation existing between cell growth, migration and cholesterol homeostasis prompted us to investigate the effect of the new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin (BAY W 6228) on these cellular events. The molecule inhibited in a dose-dependent manner the migration and the replication (evaluated as cell number and nuclear incorporation of 3H-thymidine) of rat arterial SMC with IC50 values of 2.7 microM and 0.5 microM, respectively. Among the tested statins BAY W 6228 resulted to be the most potent inhibitor of cholesterol synthesis and cell proliferation. Conditions producing 80-90% inhibition of cholesterol synthesis correlate with approximately 50% inhibition of cell growth. Similar results were obtained in SMC from human femoral artery. The in vitro inhibition of cell migration and proliferation induced by BAY W 6228 (80% decrease) was completely prevented by the addition of mevalonate and partially prevented (60-80%) by farnesol and geranylgeraniol, confirming the specific role of isoprenoid metabolites-probably through a prenylated protein(s)-in regulating these cellular events. The present results provide evidence that BAY W 6228 interferes, at least in vivo, with smooth muscle cells migration and proliferation, major processes involved in atherogenesis.

Animals↗
PubMed1993

Reduction of myocardial leukocyte accumulation and myocardial infarct size following administration of BAY u3405, a thromboxane A2 receptor antagonist, in myocardial ischaemia-reperfusion injury.

We investigated the effect of BAY u3405, a thromboxane A2 receptor antagonist in pentobarbital anaesthetized rats subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham operated rats were used as controls (Sham MI/R). Survival rate, myocardial necrosis, myocardial myeloperoxidase activity (investigated as an index of leukocyte adhesion and accumulation) and serum creatine phosphokinase activity were studied. Ischaemia-reperfusion injury significantly reduced the survival rate (45%), caused a marked myocardial necrosis, increased serum creatine phosphokinase activity (Sham MI/R = 26 +/- 10.2 U/ml; MI/R = 213 +/- 19 U/ml) and produced a rise in myocardial myeloperoxidase activity in the area-at-risk and in the necrotic area (6.1 +/- 0.4 U x 10(-3)/g tissue and 6.7 +/- 0.9 U x 10(-3)/g of tissue, respectively). The administration of BAY u3405 (30 and 60 mg/kg/i.v., 30 min before occlusion) significantly increased survival rate, lowered the area of myocardial necrosis, blunted the increase in serum creatine phosphokinase activity and reduced the increase in myeloperoxidase activity in both the area-at-risk and the necrotic area. Furthermore, the protective effect of BAY u3405 was dose-dependent. These data are consistent with an involvement of TXA2 in myocardial ischaemia-reperfusion injury and suggest that BAY u3405 may represent a novel therapeutic approach to the treatment of acute ischaemia-reperfusion injury.

Animals↗
PubMed1986

[Experimental atherogenesis].

The arterial wall possesses homeostatic mechanisms which are fundamental to the maintenance of its anatomical and functional integrity. The relative or absolute insufficiency of such mechanisms can lead with time to vascular disease, not the least of which is atherosclerosis. The understanding of the physiology of the arterial wall seems therefore necessary to a better approach to the study of several pathological processes. Four cell types play a critical role in the response of the vascular wall to physiological and pathological stimuli. They are the endothelial cell, the smooth muscle cell, the monocyte/macrophage and the platelet. The ordered interaction among these cell types is responsible for the maintenance of vascular integrity and, thus, for an efficient arterial response to physiological stimuli. Thus, it can be conceptually said that atherosclerosis derives from an excessive biological response to pathological stimuli. The current knowledge on the properties and potential interactions among each of the cells present and interacting with the arterial wall in relation to physiological mechanisms and atherogenic stimuli is discussed.

Animals↗
PubMed1984

The role of endothelial injury and platelet and macrophage interactions in atherosclerosis.

Atherosclerotic lesions take two forms, the fatty streak and the fibrous plaque or complicated lesion. The former is a flat, lipid-rich lesion containing variable numbers of foam cells in the form of macrophages and/or smooth muscle. In contrast, the fibrous plaque is a proliferative lesion of smooth muscle containing variable numbers of macrophages. Associated with the smooth muscle proliferative response is the formation of connective tissue matrix and the accumulation of intracellular and extracellular lipid. The response to injury hypothesis of atherogenesis provides and approach to exploring the interactions among substances that alter endothelial function and/or structure and to investigating the relationships among endothelium, smooth muscle, platelets, macrophages, and plasma constituents. Studies of molecules potentially important in lesion development, such as mitogens derived from platelets, macrophages, and endothelium, and of the potential roles of lipids in generating these lesions and in inducing injury to the overlying endothelial cells, have begun to shed light on how these processes may occur and on approaches that may be taken to better understand and possibly prevent them. We still lack an understanding of one of the key events, endothelial injury. The many ways by which endothelial cells may be altered in relation to the hypercholesterolemic environment and to the underlying macrophages in the fatty streaks remain to be explored. Nevertheless, these approaches point the way to the development of new means for prevention, intervention, and diagnosis of atherosclerosis.

Animals↗
PubMed1980

Platelet aggregation measured by the screen filtration pressure method in hypertensive patients.

In this study platelet aggregation was measured by the screen filtration pressure method in 2 groups of hypertensives separated according to age. They were perfectly matched for levels of various "risk factors", with normotensive "controls". No significant difference in platelet aggregate filtration pressure (PAFP) was found between hypertensives and normotensives. Contrary to normotensive subjects, there was no significant increase in the PAFP values with age in the hypertensives. This might be due to the significantly higher blood urea values in the hypertensives as compared to the normotensives. An inverse relationship between blood urea concentration and PAFP values was in fact confirmed by in vivo and in vitro studies.

Adult↗
PubMed1980

Abnormal platelet aggregation measured by screen filtration pressure (sfp) in coronary heart disease: a new risk factor?

Platelet aggregate filtration pressure PAFP) has been measured in 38 male coronary heart disease patients (CHD) free from "risk factors" for the development of arteriosclerosis. Significantly (p less than 0.05) higher mean PAFP values (mmHg) were found in the CHD group as compared to the "control" group. Such finding suggests, though does not demonstrate, the "independent" role of platelet hyperaggregation in the development of CHD.

Adenosine Diphosphate↗
PubMedDate not supplied

Antiatherogenic action of nitrendipine in hypercholesterolemic rabbits: changes in aortic macrophage accumulation and smooth muscle cell phenotype.

Intimal accumulation of macrophages and changes in the phenotype and growth properties of vascular smooth muscle cells (SMCs) represent key events in the development of atherosclerotic lesions. Here we report on the in vivo effect exerted by nitrendipine on aortic tissue of cholesterol-fed rabbits. We have focused especially on the myosin heavy chain (MyHC) pattern expressed by aortic SMC, taken as a marker of cell differentiation. Using monoclonal antibodies specific to the different forms of MyHC, three differentiation steps were determined: adult, postnatal, and fetal. Nitrendipine administered in conjunction with a cholesterol-enriched diet reduced the development of atherosclerotic lesions (atherosclerosis index: 0.21 vs. 0.32 in untreated animals, p< 0.005), despite persistently high serum cholesterol levels. Compared to untreated controls, nitrendipine-treated animals displayed a decreased number of postnatal-type SMCs in the media underlying the plaque (prevalence index: 0.07 vs. 0.26, p < 0.0001 and a lower aortic cholesterol content (free cholesterol: 3.3 vs. 11.5 ng/mg, p< 0.0001; esterified cholesterol: 7.2 vs. 40.5 ng/mg, p< 0.0001). Moreover, nitrendipine treatment decreased the intimal accumulation of macrophages and fetal-type SMCs. It is conceivable that calcium antagonists may exert their antiatherogenic effect, at least in part, through cellular changes unrelated to the classical risk factors.

Animals↗
PubMedDate not supplied

Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation.

Morphologic studies resulting from events that occur during the development of the lesions of atherosclerosis were studied in chronic, diet-induced hypercholesterolemia in a series of nonhuman primates. Within 12 days of hypercholesterolemia in Macaca nemestrina, monocytes became adherent to the surface of the endothelium. These monocytes appeared to migrate subendothelially, accumulate lipid, and become lipid-laden macrophages (foam cells). Within a month, a "serofibrinous insudate" formed together with variable numbers of subendothelial lipid-laden macrophages. By the second month, foam cells increased in number, often in multilayers, to form a fatty streak. Concomitantly, the luminal surface of the arteries became increasingly irregular due to the subendothelial accumulation of foam cells. Numerous monocytes continued to attach to the endothelial surface over the fatty streaks, and many of them appeared to enter the intima and participate in the growth of the fatty streaks. Lipid-laden smooth muscle cells appeared in small numbers and formed two to four layers between the macrophages and the internal elastic lamella at 2 to 3 months. During the third month of hypercholesterolemia, endothelial cell continuity over the lipid-laden macrophages became interrupted, exposing the underlying foam cells to circulating blood. Foam cells were then readily observed in whole blood smears, suggesting that many of the lipid-laden macrophages leave the intima and enter the circulation. After 4 months, significant endothelial denudation was found in the iliac artery and many exposed macrophages were covered by adherent platelets in the form of a mural thrombus. Thus, the early components of atherosclerosis induced by chronic hypercholesterolemia centered around the monocyte-macrophage and its interaction with endothelium in the induction of the fatty streak. Subsequent changes that lead to macrophage-smooth muscle interactions, platelet-macrophage interactions, and platelet-endothelial interactions appeared to set the stage for the development of more advanced proliferative lesions.

Animals↗