tretinoin and Arteriosclerosis

Thiazolidinediones, a new class of antidiabetic drugs that increase insulin sensitivity, have been shown to be ligands for peroxisome proliferator-activated receptor gamma (PPARgamma). Recent studies demonstrating that PPARgamma occurs in macrophages have focused attention on its role in macrophage functions. In this study, we investigated the effect of thiazolidinediones on monocyte proliferation and migration in vitro and the mechanisms involved. In addition, we examined the therapeutic potentials of thiazolidinediones for injured atherosclerotic lesions. Troglitazone and pioglitazone, the two thiazolidinediones, as well as 15-deoxy-delta12,14-prostaglandin J2 inhibited in a dose-dependent manner the serum-induced proliferation of THP-1 (human monocytic leukemia cells) and of U937 (human monoblastic leukemia cells), which permanently express PPARgamma. These ligands for PPARgamma also significantly inhibited migration of THP-1 induced by monocyte chemoattractant protein-1 (MCP-1). Troglitazone and 15-deoxy-delta12,14-prostaglandin J2 significantly suppressed the mRNA expression of the MCP family-specific receptor CCR2 (chemokine CCR2 receptor) in THP-1 at the transcriptional level. Furthermore, troglitazone significantly inhibited MCP-1 binding to THP-1. Oral administration of troglitazone to Watanabe heritable hyperlipidemic (WHHL) rabbits after balloon injury suppressed acute recruitment of monocytes/macrophages and accelerated re-endothelialization. These results suggest that thiazolidinediones have therapeutic potential for the treatment of diabetic vascular complications.

Topics: Alitretinoin; Angioplasty, Balloon; Animals; Aorta; Arteriosclerosis; Binding, Competitive; Cell Line; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokine CCL2; Chromans; Dose-Response Relationship, Drug; Endothelium, Vascular; Gene Expression Regulation; Humans; Macrophages; Male; Monocytes; Pioglitazone; PPAR gamma; Prostaglandin D2; Rabbits; Receptors, CCR2; Receptors, Chemokine; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiazolidinediones; Time Factors; Tretinoin; Troglitazone; Vascular Endothelial Growth Factor A; Wound Healing

Retinoids regulate a variety of biological processes and play an important role in cell differentiation and proliferation. All-trans retinoid acid (atRA) is known to inhibit smooth muscle cell growth and thus is supposed to have favorable effects on the incidence of restenosis after percutaneous coronary interventions. The broad biological spectrum, however, leads to numerous severe side effects which limit the clinical use of a systemic application of atRA. In order to avoid systemic side effects, local delivery of atRA is preferable. The aim of this study was to evaluate the effects of atRA on the response to injury in a second-injury model of experimental balloon angioplasty.. After induction of a fibromuscular plaque in the right carotid artery of 40 New Zealand rabbits, 35 animals underwent balloon angioplasty of the preformed plaque formation. Subsequent local atRA delivery (10 ml, 10 microM) with the double-balloon catheter was performed in 15 animals. Five animals received vehicle only as sham controls, and five animals were solely electrostimulated, 15 animals served as control group with balloon angioplasty only. Vessels were excised 7 days (n=15) and 28 days (n=30) after intervention. Immunocytochemistry with antibodies against smooth muscle alpha-actin and myosin, bromodeoxyuridine, macrophages, collagen I and III and von Willebrand factor was performed. Quantitative analysis was done by computerized morphometry.. After local atRA delivery in vivo, the extent of stenosis was markedly reduced with 21.7+/-8.3% (mean+/-S.D.) 4 weeks after intervention compared to 31.8+/-13.4% in balloon-dilated animals (P=0.0937). Both a reduced early neointimal proliferation (P=0.0002) and an increase in overall vessel diameter (4 weeks after intervention, P=0.0264) contributed to a limitation of restenosis in atRA-treated animals. Immunocytochemistry revealed a more intense alpha-actin staining pattern after local atRA therapy indicating redifferentiating effects of atRA on vascular smooth muscle cells.. Local delivery of atRA led to limitation of restenosis formation in this animal model. The concept of a local atRA therapy might be a promising way to exploit the potential of atRA for vascular indications while minimizing the severe side effects of systemic retinoid therapy.

Topics: Actins; Administration, Topical; Angioplasty, Balloon; Animals; Arteriosclerosis; Carotid Stenosis; Cell Division; Collagen; Myosins; Rabbits; Secondary Prevention; Tretinoin; Tunica Intima

Thioretinamide was conjugated to coenzyme B12 to produce thioretinaco. Thioretinamide, thioretinaco, and coenzyme B12 were injected weekly into Rattus rattus that were also given atherogenic doses of homocysteine thiolactone. The presence or absence of lesions in aorta-intercostal artery junctions was examined. Control rats injected with homocysteine thiolactone (CON-Hcy) had 56.6 +/- 5.8% lesions when compared to 34.8 +/- 3.4% in control rats injected with saline (CON-Sal). Rats that received homocysteine thiolactone injection with thioretinamide (NHTR-Hcy), thioretinaco ((NHTR)2B12-Hcy), and coenzyme B12 (B12-Hcy) had 30.1 +/- 4.2%, 27.5 +/- 3.5%, and 22.8 +/- 3.0% lesions, respectively. These lesion rates were not different from those of rats receiving thioretinamide (NHTR-Sal), thioretinaco ((NHTR)2B12-Sal), and coenzyme B12 (B12-Sal) which were 31.3 +/- 1.8%, 29.8 +/- 3.9%, and 32.0 +/- 4.6%, respectively. In this study the percentage of intercostal artery lesions in rats receiving thioretinamide and homocysteine (NHTR-Hcy), coenzyme B12 and homocysteine (B12-Hcy), and thioretinaco and homocysteine ((NHTR)2/B12-Hcy) were significantly lower, 53.2%, 48.6%, and 40.3% respectively, compared to than that of the control group receiving homocysteine (CON-Hcy). Thioretinaco, thioretinamide, and coenzyme B12 provided protective effects against the atherogen homocysteine thiolactone. A new method for the synthesis of the N-substituted derivative of homocysteine thiolactone, thioretinamide, was also reported.

Topics: Animals; Aorta, Thoracic; Arterial Occlusive Diseases; Arteries; Arteriosclerosis; Cobamides; Female; Food; Homocysteine; Magnetic Resonance Spectroscopy; Mass Spectrometry; Propylene Glycol; Rats; Tissue Fixation; Tretinoin; Vitamin B 12; Weight Gain

Topics: Arteriosclerosis; CD36 Antigens; Cell Line; Cells, Cultured; Fibrinolytic Agents; Gene Expression Regulation; Humans; Lipoproteins, LDL; Monocytes; Muscle, Smooth, Vascular; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Reverse Transcriptase Polymerase Chain Reaction; Rosiglitazone; Signal Transduction; Thiazoles; Thiazolidinediones; Transcription Factors; Tretinoin

Matrix Gla Protein (MGP) is a small protein which is thought to be an inhibitor of tissue calcification and a regulator of cell differentiation. In this study we have examined the transcriptional regulation of MGP within rat vascular smooth muscle cells (VSMCs). We found that MGP transcription is downregulated by retinoic acid and transforming growth factor beta (TGF beta) whereas it is upregulated by vitamin D3 and cyclic AMP.

Topics: Animals; Arteriosclerosis; Calcinosis; Calcium-Binding Proteins; Cholecalciferol; Cyclic AMP; Down-Regulation; Extracellular Matrix Proteins; Gene Expression Regulation; Humans; Matrix Gla Protein; Muscle, Smooth, Vascular; Rats; Transcription, Genetic; Transforming Growth Factor beta; Tretinoin; Up-Regulation

Rat aortic smooth muscle cells (SMCs) cultured from intimal thickening 15 days after endothelial injury (IT-15), unlike those of normal media, show a monolayered, epithelioid phenotype and high levels of cellular retinol binding protein-1 (CRBP). Epithelioid clones obtained from the normal media suggest a "mosaicism" of arterial SMCs. Intimal cell homeostasis from the balance of proliferation and apoptosis is critical for the progression of vascular lesions. All-trans retinoic acid (tRA) reduced [(3)H]thymidine incorporation and G(1)-->S phase progression of IT-15 and epithelioid clone but not of normal media and IT 60 days after injury (IT-60) SMCs. Hoechst staining, flow cytometry, and ligation-mediated polymerase chain reaction showed an increased susceptibility of IT-15 and epithelioid clone to tRA and cis-diaminedichloroplatinum II (CDDP)-induced apoptosis and cytotoxicity compared with normal media and IT-60 cells. The latter retained an increased susceptibility to tRA-induced apoptosis compared with normal media SMCs. tRA-induced apoptosis associated with an increased ratio of bax to bcl-2 by bax overexpression and cleavage of caspase-3. Anti-CRBP but not anti-IgG antibody prevented tRA-induced apoptosis and changes in related signaling molecules but not CDDP effects. Our findings support the relevant role of phenotypic heterogeneity in the determining proliferative as well as apoptotic behavior of arterial SMCs.

Topics: Animals; Aorta; Apoptosis; Arteriosclerosis; Blotting, Western; Cell Cycle; Cell Division; Cell Survival; Cells, Cultured; Cisplatin; Cytoskeletal Proteins; Fluorescent Antibody Technique; Male; Muscle, Smooth, Vascular; Phenotype; Rats; Rats, Wistar; Tretinoin

All-trans-retinoic acid (atRA) has potent in vitro effects on a number of processes involved in vascular injury and repair, such as modulating smooth muscle cell (SMC) proliferation and inducing SMC differentiation, and may play an important role in the in vivo response to vascular injury. We hypothesized that atRA would limit restenosis after balloon angioplasty through SMC-modulated changes in plaque size and vessel geometry. Balloon angioplasty was performed on rabbits with focal femoral atherosclerosis randomized to treatment with atRA or saline. At 28 days after balloon angioplasty, minimal luminal diameter was significantly larger in the atRA group (1.24+/-0.17 versus 1.12+/-0.22 mm, P=0.02). Histomorphometry confirmed a larger lumen area (0.51+/-0.20 versus 0. 34+/-0.13 mm(2), P=0.004) in the atRA group, with no difference in absolute plaque area. Internal elastic lamina and external elastic lamina areas were significantly larger in the atRA group (0.89+/-0. 27 versus 0.66+/-0.24 mm(2), P=0.001, and 1.29+/-0.38 versus 0. 98+/-0.32 mm(2), P=0.001, respectively). Vessel sections exhibited significantly more alpha-actin and desmin immunostaining (P=0.01) in the atRA-treated group. No differences in early cellular proliferation and collagen content were detected with the use of bromodeoxyuridine. In this atherosclerotic model of vascular injury, atRA limits restenosis after balloon angioplasty by effects secondary to overall vessel segment enlargement at the angioplasty site rather than by effects on plaque size or cellular proliferation. Increased alpha-actin and desmin immunostaining suggest a possible role for phenotypic modulation of SMCs in this favorable remodeling effect.

Topics: Actins; Angioplasty, Balloon; Animals; Arteriosclerosis; Cell Division; Collagen; Desmin; Immunohistochemistry; Male; Muscle, Smooth, Vascular; Rabbits; Recurrence; Time Factors; Tretinoin

To investigate the effects of oral administration of all-trans retinoic acid (ATRA) on inhibition of intimal thickening after balloon angioplasty in the rabbit iliac artery atherosclerotic model.. Iliac atherosclerosis was induced in 24 rabbits, and balloon angioplasty was performed. At angioplasty, 24 rabbits were randomly divided into four groups (n = 6 per group): Group 1: controls not receiving oral ATRA administration; Group 2: receiving oral ATRA (0.6 mg.kg-1.d-1) administration beginning 1 week prior to angioplasty and continuing for 4 weeks; Group 3: receiving oral ATRA (0.6 mg.kg-1.d-1) administration beginning immediately after angioplasty and continuing for 4 wk; Group 4: receiving oral ATRA (0.6 mg.kg-1.d-1) administration beginning 1 wk after angioplasty and continuing for 4 wk. Values of cross-sectional area, ratio of intimal/medial area and thickness were determined by a computer-based morphometric system, and cell proliferative activity was assessed by 3H-thymidine incorporation.. Both the cross-sectional area and the ratio of intimal/medial area and thickness were significantly reduced by ATRA administration compared with control group (P < 0.01). The inhibitory effect is less potent when ATRA is administered 1 week before angioplasty. The ATRA inhibitory effect when administered 1 week after angioplasty is not different significantly form that when administered immediately after angioplasty. The 3H-thymidine incorporation was also decreased in ATRA-treated rabbits compared with controls (P < 0.01).. Oral ATRA administration can be effective in inhibiting intimal thickening after balloon angioplasty. It is reasonable that ATRA should be administered immediately after angioplasty.

Topics: Angioplasty, Balloon; Animals; Arteriosclerosis; Hyperplasia; Iliac Artery; Male; Rabbits; Random Allocation; Tretinoin; Tunica Intima

The formation of foam cells from macrophages in the arterial wall is characterized by dramatic changes in lipid metabolism, including increased expression of scavenger receptors and the uptake of oxidized low-density lipoprotein (oxLDL). We demonstrate here that the nuclear receptor PPARgamma is induced in human monocytes following exposure to oxLDL and is expressed at high levels in the foam cells of atherosclerotic lesions. Ligand activation of the PPARgamma:RXRalpha heterodimer in myelomonocytic cell lines induces changes characteristic of monocytic differentiation and promotes uptake of oxLDL through transcriptional induction of the scavenger receptor CD36. These results reveal a novel signaling pathway controlling differentiation and lipid metabolism in monocytic cells, and suggest that endogenous PPARgamma ligands may be important regulators of gene expression during atherogenesis.

Topics: Alitretinoin; Animals; Arteriosclerosis; CD36 Antigens; Cell Differentiation; Dimerization; Foam Cells; HL-60 Cells; Humans; Ligands; Lipoproteins, LDL; Macrophages; Membrane Proteins; Mice; Mice, Transgenic; Monocytes; Promoter Regions, Genetic; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Receptors, Immunologic; Receptors, Lipoprotein; Receptors, Retinoic Acid; Receptors, Scavenger; Retinoid X Receptors; Rosiglitazone; Scavenger Receptors, Class B; Signal Transduction; Thiazoles; Thiazolidinediones; Transcription Factors; Transcriptional Activation; Tretinoin

We investigated the oxidative state of low-density lipoprotein (LDL) in patients with beta-thalassemia to determine whether there was an association with atherogenesis. Conjugated diene lipid hydroperoxides (CD) and the level of major lipid antioxidants in LDL, as well as modified LDL protein, were evaluated in 35 beta-thalassemia intermedia patients, aged 10 to 60, and compared with age-matched healthy controls. Vitamin E and beta-carotene levels in LDL from patients were 45% and 24% of that observed in healthy controls, respectively. In contrast, the mean amount of LDL-CD was threefold higher and lysil residues of apo B-100 were decreased by 17%. LDL-CD in thalassemia patients showed a strong inverse correlation with LDL vitamin E (r = -0.784; P <.0001), while a negative trend was observed with LDL-beta-carotene (r = -0.443; P =.149). In the plasma of thalassemia patients, malondialdehyde (MDA), a byproduct of lipid peroxidation, was increased by about twofold, while vitamin E showed a 52% decrease versus healthy controls. LDL-CD were inversely correlated with plasma vitamin E (r = -0.659; P <.0001) and correlated positively with plasma MDA (r = 0.621; P <. 0001). Plasma ferritin was positively correlated with LDL-CD (r = 0.583; P =.0002). No correlation was found between the age of the patients and plasma MDA or LDL-CD. The LDL from thalassemia patients was cytotoxic to cultured human fibroblasts and cytotoxicity increased with the content of lipid peroxidation products. Clinical evidence of mild to severe vascular complications in nine of the patients was then matched with levels of LDL-CD, which were 36% to 118% higher than the mean levels of the patients. Our results could account for the incidence of atherogenic vascular diseases often reported in beta-thalassemia patients. We suggest that the level of plasma MDA in beta-thalassemia patients may represent a sensitive index of the oxidative status of LDL in vivo and of its potential atherogenicity.

Topics: Adolescent; Adult; Apolipoprotein B-100; Apolipoproteins B; Arteriosclerosis; beta-Thalassemia; Cells, Cultured; Child; Disease Susceptibility; Ferritins; Fibroblasts; Humans; Hypertension, Pulmonary; Incidence; Lipid Peroxidation; Lipoproteins, LDL; Malondialdehyde; Middle Aged; Oxidation-Reduction; Oxidative Stress; Risk; Tretinoin; Vitamin E

In order to study the relation of homocysteine and lipid metabolism to atherogenesis, rabbits were fed a synthetic atherogenic diet and treated with parenteral thioretinaco (N-homocysteine thiolactonyl retinamido cobalamin), thioretinamide (N-homocysteine thiolactonyl retinamide) or homocysteine thiolactone hydrochloride. All three substances were found to increase dietary atherogenesis. Thioretinaco and thioretinamide increase total homocysteine of serum, but there is no effect of parenteral homocysteine thiolactone hydrochloride on serum homocysteine. The synthetic diet with corn oil significantly lowers serum homocysteine, compared either to baseline chow diet or to the synthetic diet with butter. Atherogenesis is correlated with total homocysteine, total cholesterol and LDL + VLDL cholesterol, and serum homocysteine is correlated with total cholesterol, LDL + VLDL, and HDL cholesterol in the total sample. Both synthetic diets elevate serum cholesterol, triglycerides and LDL + VLDL, but not HDL, compared to baseline values. Thioretinamide causes significant elevation of cholesterol and LDL + VLDL, compared to controls. The results show that increased dietary saturated fat and cholesterol cause deposition of lipids within the arteriosclerotic plaques produced by homocysteine, converting fibrous to fibrolipid plaques. Facilitation of atherogenesis is attributed to the effect of homocysteine on artery wall, either from parenteral homocysteine or from the increased synthesis of homocysteine from methionine, produced by thioretinaco and thioretinamide.

Topics: Animals; Arteriosclerosis; Diet, Atherogenic; Homocysteine; Lipids; Muscle, Smooth, Vascular; Rabbits; Tretinoin; Vitamin B 12

Inverse alterations in plasma levels of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are recognized side effects of systemic treatment with the synthetic retinoids isotretinoin and etretinate. The mass quotients of total plasma cholesterol and high-density lipoprotein cholesterol as well as low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are well-established predictive risk factors of cardiovascular disease. We evaluated and compared these lipoprotein cholesterol ratios of 80 patients treated systemically with isotretinoin (13-cis-retinoic acid) and 81 patients treated with etretinate (aromatic retinoid). Lipoprotein cholesterol data were derived from 5 lipid studies on isotretinoin, including our own results, and 4 published lipid studies on etretinate. For all isotretinoin and etretinate lipid studies, significant increases in the mean plasma levels of total cholesterol and low-density lipoprotein cholesterol and significant decreases in the mean concentration of high-density lipoprotein cholesterol were demonstrated. In comparison with etretinate, oral isotretinoin gave rise to a nearly twofold percent increase of both lipoprotein cholesterol ratios from pretreatment levels. Furthermore, for isotretinoin, an approximately linear dose-related increase of the ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol could be observed. If sustained over long periods, the mean differential rise of the ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol of 0.92 +/- 0.51 for isotretinoin and 0.56 +/- 0.10 for etretinate indicates an increased risk of cardiovascular disease for both retinoids. Etretinate could be identified as the less harmful retinoid for prolonged oral therapy.

Topics: Arteriosclerosis; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Etretinate; Humans; Isotretinoin; Retinoids; Risk; Tretinoin

Since systemic administration of synthetic retinoids was introduced into dermatology and oncology, side-effects of synthetic vitamin-A derivatives on lipid and lipoprotein metabolism have become apparent. Retinoids of the first and second generation, 13-cis-retinoic acid and etretinate, are capable of inducing secondary hyperlipoproteinemias. For further evaluation of the atherogenic risk of retinoid-induced hyperlipoproteinemias, the most relevant effects of natural and synthetic retinoids on lipid metabolism as well as the interactions between lipid and retinoid metabolism are considered in this review.

Topics: Arteriosclerosis; Biotransformation; Cholesterol; Chylomicrons; Etretinate; Humans; Hyperlipoproteinemias; Lipids; Lipoproteins; Retinoids; Retinol-Binding Proteins; Tretinoin; Triglycerides; Vitamin A

Topics: Adolescent; Adult; Aged; Amniocentesis; Amniotic Fluid; Arteriosclerosis; Ascorbic Acid; Child; Child, Preschool; Chromosome Aberrations; Dementia; Female; Folic Acid; Glutathione; Humans; Infant; Middle Aged; Mutagens; Neoplasms; Pregnancy; Tretinoin