transforming-growth-factor-beta and Aortic-Coarctation

Topics: Aortic Coarctation; Arteries; Biomarkers; Elasticity; Humans; Transforming Growth Factor beta; Vascular Stiffness; Vasodilation

Benazepril, an angiotensin-converting enzyme (ACE) inhibitor, has been used to treat hypertension, congestive heart failure, and chronic renal failure. However, its biological activity and mechanism of action in inflammation are not fully identified. The present study was designed to determine the in vivo anti-inflammatory effects of benazepril on LV hypertrophy in rats.. LV hypertrophy was produced in rats by abdominal aortic coarctation. They were then divided into the following groups: sham operation; LV hypertrophy; LV hypertrophy+benazepril (1mg/kg in a gavage, once a day for 4 weeks). Both morphological assays (hemodynamic and hemorheological measurement; LV hypertrophy assessment), and molecular assays (protein levels of Collagen type I/III, TNF-α and VCAM-1; TGF-β gene expression; NF-κB or Smad activation; intracellular ROS production) were performed.. The following effects were observed in rats treated with benazepril: (1) marked improvements in hemodynamic and hemorheological parameters; (2) significant reductions in LV hypertrophy, dilatation and fibrosis; (3) significantly attenuated protein levels of Collagen type I/III, TGF-β, TNF-α and VCAM-1, NF-κB or Smad activation, as well as intracellular ROS production.. These results suggest that the anti-inflammatory properties of benazepril may be ascribed to their down-regulation of both NF-κB and TGF-β signaling pathways by acting on the intracellular ROS production in rats with LV hypertrophy, thus supporting the use of benazepril as an anti-inflammatory agent.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Aorta; Aortic Coarctation; Benzazepines; Blood Pressure; Collagen Type I; Collagen Type III; Enzyme Activation; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Inflammation; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

Despite repair, a significant proportion of patients with coarctation of the aorta (CoA) present with late hypertension. Increased gene expression of aortic wall collagen and vascular smooth muscle cell markers occurs in the presence of hypertension. Before repair, a patent ductus arteriosus (PDA) limits hypertension proximal to the coarctation. We hypothesize that preoperative collagen and vascular smooth muscle expression from the aortic arch in children is variable, depending on the presence or absence of a PDA.. We analyzed the expression patterns of collagen and vascular smooth muscle cell markers in 25 children with CoA using a quantitative polymerase chain reaction. Aortic arch tissue proximal to the CoA was normalized to descending aortic tissue distal to the coarctation. Collagen-I, transforming growth factor-β, elastin, and calponin were analyzed.. At repair, 19 patients were aged younger than 3 months (14 with a PDA, 5 with a ligamentum arteriosum), and the remaining 6 were older than 1 year. There was no difference in age or weight between infants with or without a PDA. Infants without a PDA had the greatest difference in collagen-I expression compared with infants with a PDA (7.0 ± 1.6-fold vs 0.8 ± 1.1-fold, p = 0.01). Expression of transforming growth factor-β (4.3 ± 1.4 vs 2.6 ± 2.3, p = 0.01) and calponin (3.7 ± 0.7 vs 0.6 ± 1.1, p = 0.05) was lower from infants with vs without a PDA.. Our findings provide evidence of preoperative changes in the aortic arch before repair, particularly in the absence of a PDA.

Topics: Aorta, Thoracic; Aortic Coarctation; Calcium-Binding Proteins; Calponins; Child; Child, Preschool; Collagen Type I; Echocardiography; Female; Follow-Up Studies; Gene Expression Regulation; Humans; Hypertension; Infant; Infant, Newborn; Male; Microfilament Proteins; Muscle, Smooth, Vascular; Prognosis; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA; Transforming Growth Factor beta; Vascular Surgical Procedures

The mechanisms underlying cardiac fibrosis in hypertension are yet to be defined, although inflammatory cells, fibroblasts, and cytokines have been implicated. Here, we investigated the role of interleukin-4 (IL-4) in cardiac fibrosis, which is elevated in the hypertensive heart. IL-4 has been shown to be pro-fibrotic in the liver and the lung, but its role in cardiac fibrosis has not been investigated.. Cardiac fibrosis was induced in mice by constricting the aorta between the two carotid arteries. Fourteen days later marked left ventricular fibrosis developed together with expression of IL-4. Anti-IL-4 neutralizing antibodies attenuated this fibrosis without affecting blood pressure or expression of the transforming growth factor-beta system. The reduction in fibrosis was associated with reductions in interstitial fibroblasts and macrophages together with reductions in proliferating cells and expression of monocyte chemoattractant protein-1 (MCP-1). Since mast cells are a source of IL-4, we also assessed their role in fibrosis. Cromolyn, a mast cell inhibitor attenuated mast cell degranulation as well as IL-4 mRNA expression and cardiac fibrosis without affecting blood pressure. Treatment with Cromolyn also reduced interstitial fibroblasts and macrophages in regions of developing fibrosis as well MCP-1 expression.. This study demonstrates for the first time that IL-4, most likely produced by mast cells in the heart during pressure overload, is a significant contributor to cardiac fibrosis. Targeting this cytokine may be a useful therapeutic strategy to limit cardiac fibrosis.

Topics: Animals; Aortic Coarctation; Cell Proliferation; Fibrosis; Hypertension; Interleukin-4; Macrophages; Male; Mast Cells; Mice; Mice, Inbred C57BL; Myocardium; Reactive Oxygen Species; Transforming Growth Factor beta

A porcine aortic coarctation model was used to examine regulation of gene expression in early hypertensive vascular remodeling. Aortic segments were collected proximal (high pressure) and distal (low pressure) to the coarctation after 2 wk of sustained hypertension (mean arterial pressure>150 mmHg). Porcine 10K oligoarrays used for gene expression profiling of the two regions of aorta revealed downregulation of cytoskeletal and upregulation of extracellular region genes relative to the whole genome. A genomic database search for transforming growth factor-beta (TGF-beta) control elements showed that 19% of the genes that changed expression due to hypertension contained putative TGF-beta control elements. Real-time RT-PCR and microarray analysis showed no change in expression of TGF-beta1, TGF-beta2, TGF-beta3, or bone morphogenetic proteins-2 and -4, yet immunohistochemical staining for phosphorylated SMAD2, an indicator of TGF-beta signaling, and for phosphorylated SMAD1/5/8, an indicator of signaling through the bone morphogenetic proteins, showed the highest percentage of positively stained cells in the proximal aortic segments of occluded animals. For TGF-beta signaling, this increase was significantly different than for sham-operated controls. Western blot analysis showed no difference in total TGF-beta1 protein levels with respect to treatment or aortic segment. Immunohistochemistry showed that the protein levels of latency-associated peptide was decreased in proximal segments of occluded animals. Collectively, these results suggest that activation of TGF-beta, but not altered expression, may be a major mechanism regulating early hypertensive vascular remodeling.

Topics: Animals; Aorta; Aortic Coarctation; Blotting, Western; Bone Morphogenetic Proteins; Cell Differentiation; Databases, Genetic; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Hypertension; Immunohistochemistry; Muscle, Smooth, Vascular; Oligonucleotide Array Sequence Analysis; Phosphorylation; Polymerase Chain Reaction; Regional Blood Flow; Signal Transduction; Smad Proteins; Swine; Swine, Miniature; Transforming Growth Factor beta; Ultrasonography, Doppler, Color

SMAD proteins have recently been identified as the first family of putative transforming growth factor-beta1 (TGF-beta1) signal transducers. This study was to investigate the effects of TGF-beta1 and signal protein Smad3 on rat cardiac hypertrophy.. The incorporation of [(3)H]-leucine was measured to determine the hypertrophy of cardiomyocyte incubated with different doses of TGF-beta1 in cultured neonatal cardiomyocytes. The model of rat cardiac hypertrophy was produced with constriction of the abdominal aorta. At different times after the operation, rats were killed, and their left ventricular mass index (LVMI) determined. The mRNA expression of TGF-beta1 and Smad3 of cultured cells and hypertrophic left ventricles were assessed by RT-PCR. The protein expression of Smad3 was assessed by Western blot.. In cultured neonatal cardiomyocytes, TGF-beta1 significantly promoted incorporation of [(3)H]-leucine. With the concentration of 3 pg/L, it increased the expression of Smad3 in mRNA and protein levels after 15 minutes, and continued for up to 8 hours of cultured cardiomyocytes. The LVMI and the expression of TGF-beta1 (mRNA) and Smad3 (mRNA and protein) of hypertrophic left ventricle were increased by day 3 after the operation and continued to the 4th week. The peak expression of these was in the second week after operation.. TGF-beta1 has positive effects on rat cardiomyocyte hypertrophy. Signal protein Smad3 could be related to the pathologic progression of rat cardiac hypertrophy.

Topics: Animals; Aortic Coarctation; Cardiomegaly; Cells, Cultured; DNA-Binding Proteins; Leucine; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Smad3 Protein; Trans-Activators; Transforming Growth Factor beta; Transforming Growth Factor beta1

The molecular basis of vascular response to hypertension is largely unknown. Both cellular and extracellular components are critical. In the current study we tested the hypothesis that there is a balance between vascular cell proliferation and cell death during vessel remodeling in response to hypertension.. A midthoracic aortic coarctation was created in rats to induce an elevation of blood pressure proximal to the coarctation. The time course was 1 and 3 days and 1, 2, and 4 weeks for the study of the proximal aorta. Ribonuclease protection assay and Western blot analysis were used to evaluate gene expression of growth and apoptosis-related cytokines with two sets of multiple probes, rCK-3 and rAPO-1. Cell proliferation was determined with BrdU (5-bromo-2'-deoxyuridine) incorporation. Apoptosis was examined with TUNEL (transferase-mediated dUTP nick end-labeling). Morphometry was performed on histologic sections.. Coarctation produced hypertension in the proximal aorta, 118 +/- 9 mm Hg versus 94 +/- 6 mm Hg in controls (P <.002). Both messenger RNA and protein levels of transforming growth factor (TGF)-beta1 and TGF-beta3 were increased (P <.005 vs controls). Messenger RNA and protein of Bcl-xS and Fas ligand, known as proapoptotic factors, were both reduced after coarctation (P <.005 vs controls). There was increased BrdU incorporation at 3 days and 1 and 2 weeks (P <.001 vs controls). There were no remarkable changes in the apoptosis rate until 4 weeks later.. Cell proliferation was stimulated at 3 days, and apoptosis was halted until 4 weeks. These changes were associated with upregulation of TGF-beta and downregulation of Bcl-xS and Fas ligand gene expression. These findings suggest that a coordinated regulation of cell proliferation and cell death contributes to arterial remodeling in response to acute sustained elevation of blood pressure. Cell proliferation precedes apoptosis by 2 weeks in this procedure.

Topics: Animals; Aortic Coarctation; bcl-X Protein; Cell Death; Cell Division; Down-Regulation; Fas Ligand Protein; Gene Expression; Hypertension; Membrane Glycoproteins; Muscle, Smooth, Vascular; Proto-Oncogene Proteins c-bcl-2; Rats; RNA, Messenger; Transforming Growth Factor beta; Up-Regulation

The role of angiotensin II via the angiotensin type 1 or type 2 receptor in the development of cardiac hypertrophy was determined in adult male Sprague-Dawley rats subjected to coarctation of the abdominal aorta. Five groups of animals were studied: coarctation, coarctation plus DuP 753, coarctation plus PD 123319, sham plus DuP 753, or sham operation. Type 1 receptor blockade was accomplished with DuP 753 given in the drinking water and type 2 blockade with PD 123319 delivered by osmotic minipumps beginning with the day of surgery until 72 hours after aortic coarctation. Mean carotid blood pressures and the carotid-femoral artery blood pressure gradients were not different among coarctation, coarctation plus DuP 753, and coarctation plus PD 123319 animals. However, ratios of heart weight to body weight were higher in coarctation (4.95 +/- 0.8) or coarctation plus PD 123319 (4.52 +/- 0.5) than in sham animals (3.6 +/- 0.4; P < .005 and .05, respectively). In coarctation plus DuP 753-treated animals heart weight-body weight ratios were not different from sham or sham plus DuP 753 animals (3.9 +/- 0.4 versus 3.6 +/- 0.4 or 3.3 +/- 0.08, respectively). Type 1 receptor mRNA levels were significantly increased in the coarctation group, with the highest levels in the coarctation plus DuP 753 and sham plus DuP 753 groups. To determine whether growth factors were involved in the hypertrophic process, we measured transforming growth factor-beta 1 mRNA levels. Northern analysis demonstrated a twofold increase in coarctation animals compared with sham or coarctation plus DuP 753-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Animals; Aortic Coarctation; Atrial Natriuretic Factor; Biphenyl Compounds; Cardiomegaly; Gene Expression Regulation; Imidazoles; Losartan; Male; Rats; Rats, Sprague-Dawley; Receptors, Angiotensin; Tetrazoles; Transforming Growth Factor beta