-
[show abstract]
[hide abstract]
ABSTRACT: The angiotensin II type 2 (AT2) receptor promotes apoptosis and inhibits cell proliferation. In the present study, we investigated the role of the AT2 receptor in vascular repair and remodeling following severe vascular injury using AT2 knockout (AT2KO) mice. Left femoral arteries of AT2KO mice and wild-type (WT) control mice were injured by a 0.38 mm steel wire inserted from the lumen. Twenty-eight days after the injury, a concentric vascular wall thickening, composed largely of neointima, was noted both in AT2KO and WT mice. The area occupied by the neointima and the cell count within it were not different in the two mouse strains. However, the area of the medial layer and the cell count within it were significantly larger in AT2KO mice than in WT mice. A BrdU incorporation assay showed that the proliferative activity was high in the neointima but it was not different between the strains. On the other hand, apoptosis assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) was significantly inhibited in the neointima and the media of AT2KO mice compared to the levels in WT mice. However, the number of TUNEL-positive cell was much smaller in the neointima than in the medial layer in both strains. Taken together, these results indicate that AT2 receptors promote the apoptosis of vascular cells but have no net effect on the neointimal cell growth or luminal narrowing after wire injury. The AT2 receptor may be involved in the control of medial layer thickness, at least in part, through medial cell apoptosis.
Hypertension Research 07/2008; 31(6):1241-9. · 2.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Bach1 is a stress-responsive transcriptional factor that is thought to control the expression levels of cytoprotective factors, including heme-oxygenase (HO)-1. In the present study, we investigated the roles of Bach1 in the development of left ventricular (LV) hypertrophy and remodeling induced by transverse aortic constriction (TAC) in vivo using Bach1 gene-deficient (Bach1(-/-)) mice. TAC for 3 weeks in wild-type control (Bach1(+/+)) mice produced LV hypertrophy and remodeling manifested by increased heart weight, histological findings showing increased myocyte cross-sectional area (CSA) and interstitial fibrosis (picro Sirius red staining), reexpressions of ANP, BNP, and betaMHC genes, and echocardiographic findings showing wall thickening, LV dilatation, and reduced LV contraction. Deletion of Bach1 caused significant reductions in heart weight (by 16%), CSA (by 36%), tissue collagen content (by 38%), and gene expression levels of ANP (by 75%), BNP (by 45%), and betaMHC (by 74%). Echocardiography revealed reduced LV dimension and ameliorated LV contractile function. Deletion of Bach1 in the LV caused marked upregulation of HO-1 protein accompanied by elevated HO activity in both basal or TAC-stimulated conditions. Treatment of Bach1(-/-) mice with tin-protoporphyrin, an inhibitor of HO, abolished the antihypertrophic and antiremodeling effects of Bach1 gene ablation. These results suggest that deletion of Bach1 caused upregulation of cytoprotective HO-1, thereby inhibiting TAC-induced LV hypertrophy and remodeling, at least in part, through activation of HO. Bach1 repressively controls myocardial HO-1 expression both in basal and stressed conditions, inhibition of Bach1 may be a novel therapeutic strategy to protect the myocardium from pressure overload.
Hypertension 07/2008; 51(6):1570-7. · 6.21 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This study was designed to determine whether Bach1 gene ablation leads to suppression of atherosclerosis in apolipoprotein E (Apo E)/Bach1 double knockout (DKO) mice. Apo E/Bach1 DKO mice were generated by intercrossing Apo E knockout (KO) and Bach1 KO mice. The animals were fed a high-fat diet for 8 weeks, and the atherosclerotic plaques in the thoracic and abdominal aorta were visualized by oil red O staining. In DKO mice, the total plaque area was reduced by 32% compared with that in Apo E KO mice. In DKO mice, heme oxygenase-1 (HO-1) was upregulated in the endothelium and, to a lesser extent, in vascular smooth muscles. In atherosclerotic plaques in Apo E KO mice and DKO mice, HO-1 was abundantly expressed in the endothelium and macrophages. Urine excretion of 8-iso-prostaglandin (PG) F2alpha, a marker for lipid peroxidation, was reduced in DKO mice compared with that in Apo E KO mice. The effects of Bach1 ablation on the plaque area and 8-iso-PG F2alpha excretion were almost completely abolished by treating DKO mice with Sn protoporphyrin, an inhibitor of HO activity. Disruption of the Bach1 gene in Apo E KO mice caused inhibition of atherosclerosis through upregulation of HO-1. Inhibition of Bach1, conversely, may be a novel therapeutic strategy to treat atherosclerotic diseases.
Hypertension Research 04/2008; 31(4):783-92. · 2.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Excessive oxidative stress plays an important role in the mechanism of atherosclerosis. An increased level of reactive oxygen speices (ROS) within the vascular endothelium eventually impedes the vasodilatative and cytoprotective actions of nitric oxide (NO). Such a condition is considered to be an early feature of atherosclerosis, and is physiologically detectable as a decrease in endothelium-dependent vasodilatation. Increased intracellular ROS levels are involved in the mechanisms of hypertension, diabetes, and hyperlipidemia, all of which are major risk factors of atherosclerosis; therefore, the assessment of "oxidative status" is obviously relevant to clinical medicine. However, most of the currently available clinical tests just measure oxidized waste. Considering that the ROS level is determined by the balance between production and elimination, assessment of the ability to eliminate ROS may be a major determinant of the oxidative state and may be useful to assess individual susceptibility to atherosclerotic diseases. Focusing on heme oxygenase (HO)-1, one of the major stress defense mechanisms, we found that the capacity to upregulate HO-1 mRNA is tightly associated with the severity of coronary artery disease. Furthermore, individual differences in stress-induced HO-1 levels were determined by HO-1 gene polymorphism. We propose that clinical use of the HO-1 expression profile as a measure of tolerability against oxidative stress may be relevant in the early diagnosis of atherosclerotic diseases.
Rinsho byori. The Japanese journal of clinical pathology 09/2007; 55(8):758-63.
-
[show abstract]
[hide abstract]
ABSTRACT: Heme oxigenase-1 (HO-1) is known to be an inducible cytoprotective enzyme that copes with oxidative stress. However, changes in HO-1 expression and their association with human diseases have not been studied. To test the hypothesis that the capacity to upregulate HO-1 in response to oxidative stress is an intrinsic marker for susceptibility to coronary atherosclerosis, we assessed stimulation-induced change in HO-1 expression in blood cells in 110 patients who underwent coronary angiography, comparing the results with the extent of coronary atherosclerosis and (GT)(n) repeat polymorphism in the HO-1 gene promoter region, which is believed to affect the gene expression level. The extent of coronary atherosclerosis was assessed by coronary score. Mononuclear cells were incubated with 10 micromol/l hemin or vehicle for 4 h to maximally stimulate HO-1 expression, then the HO-1 expression level was determined by real-time polymerase chain reaction (PCR). The difference between the HO-1 mRNA levels of hemin- and vehicle-treated cells (DeltaHO-1 mRNA) was taken as an index of the capacity to upregulate HO-1 mRNA. The coefficient of variance of DeltaHO-1 mRNA was 7.2%. Consistent with previous studies, DeltaHO-1 mRNA was significantly lower in patients carrying a long (GT)(n) repeat. DeltaHO-1 mRNA negatively and significantly correlated with the coronary score (r(2)=0.50, p<0.01). In conclusion, the capacity to upregulate HO-1 expression may be determined, at least in part, by genetics, and reduced ability to induce HO-1 may be involved in the mechanism of coronary atherosclerosis.
Hypertension Research 05/2007; 30(4):341-8. · 2.58 Impact Factor
