Involvement of vascular angiotensin II-forming enzymes in the progression of aortic abdominal aneurysms in angiotensin II- infused ApoE-deficient mice.

AIM: Angiotensin (Ang) II-induced abdominal aortic aneurysm (AAA) in apoE-deficient mice has been used as a model of human AAA, but it has been unclear why the progression of AAA continues after stopping the Ang II infusion. The involvement of vascular Ang II-forming enzymes in the progression of AAA was studied. METHODS: ApoE-deficient mice were infused with Ang II (1,000 ng/kg/min) for 4 weeks and evaluated until 20 weeks after the Ang II infusion. Just after and 20 weeks after stopping the Ang II infusion, the degree of AAA, as well as the ACE and chymase activities, was evaluated. An Ang II receptor blocker (candesartan, 30 mg/kg/day) and an angiotensin-converting enzyme (ACE) inhibitor (lisinopril, 60 mg/kg/day) were given for 20 weeks after stopping the Ang II infusion. RESULTS: The aortic diameter expanded just after stopping the Ang II infusion and progressed for a further 20 weeks after the infusion was stopped. Just after stopping the infusion, aortic ACE and chymase activities were significantly increased, but only the increase in chymase activity continued until 20 weeks after the infusion was stopped. Candesartan and lisinopril significantly attenuated aortic diameter expansion. CONCLUSION: The increases in vascular Ang II-forming activities were involved in the progression of AAA after stopping the Ang II infusion.

Effects of chymase inhibitor on angiotensin II-induced abdominal aortic aneurysm development in apolipoprotein E-deficient mice.

OBJECTIVE: Chymase may play an important role in abdominal aortic aneurysm (AAA) development through matrix metalloproteinase (MMP)-9 activation. The purpose of this study was to determine whether chymase is involved in angiotensin (Ang) II-induced AAA development in apolipoprotein E (apoE)-deficient mice. METHODS AND RESULTS: In this study, Ang II (1000 ng/kg/min; vehicle group) or saline (saline group) was administered to 16-week-old, male, apoE-deficient mice for 4 weeks. To examine the effects of chymase inhibition on AAA development, oral NK3201 (30 mg/kg/day) was given for the same period as the Ang II infusion. AAAs developed at the suprarenal region of the abdominal aorta in the Ang II-treated vehicle group, but they were not observed in the saline group. On the other hand, the severity and luminal area of the AAAs in the Ang II-treated vehicle group were significantly suppressed by NK3201 treatment. MMP-9 activity was significantly lower in the Ang II-treated+NK3201-treated group than in the Ang II-treated vehicle group. Furthermore, there were significantly fewer monocyte/macrophage cells in the Ang II-treated+NK3201-treated group than in the Ang II-treated vehicle group. CONCLUSIONS: Chymase is involved in Ang II-induced AAA development in apoE-deficient mice.

Roles of chymase in stenosis occurring after polytetrafluoroethylene graft implantations.

Chymase is an important enzyme for the generation of angiotensin (Ang) II and in the activation of transforming growth factor (TGF)-beta1. Therefore, chymase may be involved in the hemodialysis access dysfunction, which is caused by intimal hyperplasia that occurs after polytetrafluoroethylene (PTFE) graft implantations. Bilateral U-shaped PTFE grafts were placed between the femoral vein and artery in dogs. Chymase inhibitor (NK3201, 1 mg/kg per day, p.o.) treatments were initiated 3 days before the operation. After the implantation, the stenosis by neointima proliferation was most frequently observed in the venous side of the PTFE grafts. In the hyperplastic neointima, myofibroblasts were the main cellular components. On the other hand, fibroblasts only occupied cellular components in a much smaller proportion in the neointima. However, these cells seem to be rich in the properties of proliferation and migration. After PTFE graft implantations, extensive accumulations of chymase-positive mast cells were found mainly in the tissue surrounding the grafts. The Ang II- and TGF-beta-positive cells were found in an adjacent section that was in close proximity to the chymase-positive cells. In contrast, the AT(1) receptors, as well as TGF-beta type II receptors, were expressed either in the neointima or in the outside adventitia of the PTFE grafts. Chymase inhibitor treatment resulted in a reduction of chymase, Ang II and TGF-beta1 expression, leading to a significant inhibition of neointimal formation. These findings indicating that an increase of chymase via promoting Ang II and TGF-beta1 generation plays a pivotal role in the neointimal formation after the implantation of PTFE grafts and also suggesting that chymase inhibition may be a new strategy that can be used to prevent PTFE graft dysfunctions in clinical settings.

The significance of chymase in the progression of abdominal aortic aneurysms in dogs.

In this study, we investigated the effect of a specific chymase inhibitor, NK3201, in the progression of abdominal aortic aneurysm in a dog experimental model. Abdominal aortic aneurysms were induced in dogs by injecting elastase into the abdominal aorta. NK3201 (1 mg/kg per day, p.o.) or a placebo was started 3 days before elastase injection and continued for 8 weeks after the injection. On abdominal ultrasound, the aortic diameter was seen to gradually expand in the placebo-treated group, but not in the NK3201-treated group. Eight weeks after elastase injection, the ratio of the medial area to the total area in the placebo-treated group was significantly smaller than that in the normal group, but it was significantly larger than that in the NK3201-treated group. In addition to chymase activity, angiotensin II-forming and matrix metalloproteinase-9 activities were significantly higher in the placebo-treated group than in the normal group; in the NK3201-treated group, all of these activities were significantly decreased. On immunohistochemical analyses, there was a significantly greater number of chymase-positive cells in the placebo-treated group than in the normal group, but the number was significantly smaller in the NK3201-treated group than in the placebo-treated group. Thus, chymase inhibition may become a useful strategy for preventing abdominal aortic aneurysms.

The effects of chymase on matrix metalloproteinase-2 activation in neointimal hyperplasia after balloon injury in dogs.

Chymase is known to generate angiotensin II in the vascular wall. In this study we investigated a novel role for chymase other than angiotensin II production in vascular proliferation after balloon injury. Chymase promoted the migration of vascular smooth muscle cells in the matrix-coated invasion chambers and activated promatrix metalloproteinase-2 obtained from the culture medium of vascular smooth muscle cells. Two weeks after balloon injury, significant neointimal formation was found in dog carotid arteries. After injury, active matrix metalloproteinase-2 was increased in parallel with the augmentation of chymase activity that was seen in the proliferating region of the vascular wall. The oral administration of NK3201 (1 mg/kg per day), a chymase inhibitor, prevented neointimal formation and significantly suppressed both active matrix metalloproteinase-2 and chymase activities 2 weeks after injury. These results suggest that chymase inhibitors can prevent the development of intimal hyperplasia via the inhibition of matrix metalloproteinase-2 activation in balloon-injured arteries.

Thiamine attenuates the hypertension and metabolic abnormalities in CD36-defective SHR: uncoupling of glucose oxidation from cellular entry accompanied with enhanced protein O-GlcNAcylation in CD36 deficiency.

BACKGROUND AND OBJECTIVES: The spontaneous hypertensive rat (SHR) is a widely studied model of hypertension that exhibits metabolic abnormalities, which share features with the human metabolic syndrome. Genetic linkage studies have revealed a defective CD36 gene, encoding a membrane fatty acid (FA) transporter, in hyperinsulinemia of the SHR. However, there is no unifying mechanism that can explain these phenotypes as a consequence of a defective CD36 gene. Impaired fatty acid uptake is compensated by increased glucose uptake. We hypothesized that (1) the abundant intracellular glucose is not oxidized proportionally and (2) the correction of the uncoupling of glucose oxidation to its cellular entry might be effective against the pathophysiology of CD36-defective SHR. Therefore, we attempted to activate glucose oxidation with the repletion of thiamine, a coenzyme for multiple steps of glucose metabolism. METHODS AND RESULTS: In one series of experiments, intracellular glucose fate was assessed by the ratio of [(14)C]glucose/[(3)H]deoxyglucose radioactivity, which suggested that glucose oxidation was uncoupled from its cellular entry in SHR. Protein O-GlcNAcylation was intense in the hearts of CD36-defective SHR compared with that of wild-type CD36 rats [Wister Kyoto rats (WKY)], indicating the shunt of glucose through the hexosamine biosynthetic pathway (HBP). In another series of studies, 4-week-old SHR were maintained with water containing 0.2% thiamine for 10 weeks. Systolic blood pressure, plasma insulin and norepinephrine levels were significantly lower in the thiamine-group, as compared with the untreated-group. In epididymal adipose tissue, thiamine repletion down-regulated the expression levels of mRNA transcripts for UDP-N-acetylglucosamine:peptide glycosyltransferase, angiotensinogen, angiotensin type 1 receptor, transforming growth factor-beta1 and plasminogen activator inhibitor-1. CONCLUSIONS: The hearts of CD36-defective SHR exhibited uncoupling of glucose oxidation from its cellular entry, accompanied with the enhanced protein O-GlcNAcylation, suggesting increased glucose shunt through the HBP. Thiamine repletion in CD36-defective SHR resulted in (1) the correction of the uncoupling of glucose oxidation to its cellular entry, concomitant with reduced protein O-GlcNAcylation, (2) the down-regulation of the expression of mRNAs involved in HBP, the renin-angiotensin system and adipokines in epididymal adipose tissue, and (3) the attenuation of the hypertension and hyperinsulinemia. We propose that interventions targeting glucose oxidation with thiamine repletion may provide a novel adjunctive approach to attenuate metabolic abnormalities and related hypertension.

Pathological roles of angiotensin II produced by mast cell chymase and the effects of chymase inhibition in animal models.

The discovery of a new angiotensin II (Ang II) pathway generated by mast cell chymase has highlighted new biological functions for Ang II that is not related to the classic renin-angiotensin system (RAS). The conversion of Ang I to II occurs not only via the plasma angiotensin converting enzyme (ACE) or tissue ACE but also via chymase produced in the mast cells of humans, monkeys, dogs, and hamsters. The conversion by chymase has been especially found in morbid tissues following the migration of mast cells. The newly discovered functions of chymase are discussed in this review. During the vascular narrowing that occurs after vein grafting or balloon injury in dogs, chymase activity and Ang II concentrations along with intimal proliferation are significantly increased and chymase inhibitors completely suppressed these increase, though ACE inhibitors are ineffective. Similar results have also been confirmed in the dog arteriovenous fistula stenosis model. In both human and animal aneurysmal aortas, chymase activity is significantly increased, and chymase inhibitor has been shown to prevent the development of aneurysms in dogs. Chymase is activated in diseased hearts, and chymase inhibitors reduce both the mortality rates after acute myocardial infarction and the cardiac fibrosis that leads to the development of cardiomyopathy in hamsters. Chymase is also a pro-angiogenic factor, since the injection of chymase strongly facilitates angiogenesis in hamsters. We propose that chymase inhibitors are effective in the prevention of multiple cardiovascular disorders, especially at the local event level without any effect on the systemic blood pressure.

Role of chymase-dependent angiotensin II formation in monocrotaline-induced pulmonary hypertensive rats.

Angiotensin II-forming chymase is expressed in the pulmonary arteries of the monocrotaline-induced pulmonary hypertensive rats, but its actual role is unclear. We studied chymase-dependent angiotensin II formation in the pulmonary arteries of the monocrotaline-induced pulmonary hypertensive rats and observed the effects of an angiotensin II receptor blocker on vascular remodeling. Four weeks after the administration of monocrotaline (60 mg/kg, s.q.), echocardiographic, hemodynamic, morphometric and biochemical analyses were performed. Age-matched rats were used as controls. To evaluate the effects of an angiotensin II receptor blocker, 2 wk after beginning of monocrotaline treatment, the rats were given candesartan (10 mg/kg per day) or placebo for 2 wk. In the monocrotaline-induced pulmonary hypertensive rats, the elevated systolic pulmonary arterial pressure and right ventricular hypertrophy were observed. Medial hypertrophy of lung arterioles was also observed. Chymase activity and angiotensin II concentration, but not angiotensin-converting enzyme activity, were significantly increased in the lung. In the angiotensin II receptor blocker-treated group, both systolic pulmonary arterial pressure and right ventricular hypertrophy were significantly reduced, and arteriolar hypertrophy was also prevented. Thus, angiotensin II-forming chymase may play a role in the proliferation of the medial layer in the lung arterioles of monocrotaline-induced pulmonary hypertensive rats.

Effects of chymase on the macular region in monkeys and porcine muller cells: probable involvement of chymase in the onset of idiopathic macular holes.

OBJECTIVES: To investigate chymase involvement in idiopathic macular hole onset, the effects of chymase on monkey eyes and cultured Muller cells were investigated. METHODS: Immunohistochemistry using antinestin and antiglial fibrillary acidic protein antibodies was performed in a normal monkey eye. After chymase was injected into the monkey vitreous, histological changes in the retina were evaluated using the TdT-mediated dUTP nick-end labeling (TUNEL) assay. Expression of c-kit, a stem cell factor receptor, and nestin was examined in porcine Muller cells cultured with basic fibroblast growth factor. The effects of chymase on proliferation and TUNEL staining in Muller cells were also examined. RESULTS: The number of nestin and glial fibrillary acidic protein-positive cells was higher in the macula than in other regions. Thickening of the posterior hyaloid membrane and some apoptotic cells were found in the macula of chymase-treated eyes. The expression of c-kit and nestin in Muller cells was shown and enhanced when cultured with basic fibroblast growth factor. Exposure to chymase inhibited Muller cell proliferation and produced TUNEL-positive cells. CONCLUSIONS: There might be Muller cells possessing atypical properties near the macular region and chymase might cause fibrosis and apoptosis through these cells. These findings suggest that increased chymase activity may result in idiopathic macular hole onset.

Expression of chymase-positive cells in gastric cancer and its correlation with the angiogenesis.

BACKGROUND AND OBJECTIVES: Chymase is expressed in mast cells and induces angiogenesis via activation of angiotensin II and matrix metalloproteinase-9. However, it has been unclear whether chymase is involved in the pathophysiology of angiogenesis in gastric cancer. To clarify the contribution of chymase to angiogenesis in gastric cancer, we assessed the relationship between chymase-positive cells and tumor angiogenesis. METHODS: We evaluated chymase-positive cells and microvessels using anti-human chymase and anti-CD34 antibodies in 168 cases of gastric cancer, respectively. RESULTS: Chymase-positive cells in gastric tumor region were significantly higher than the cells in normal region. The number of chymase-positive cells in the undifferentiated type of gastric tumor region was significantly higher than the one in the differentiated type. Specimens from patients with advanced histological stages of disease had more chymase-positive cells than those with early-stage disease. There was a significant positive correlation between chymase-positive cells and microvessels in gastric cancer specimens. Postoperative survival curves revealed that patients with a high number of chymase-positive cells had a poor prognosis. CONCLUSIONS: These results suggest that accumulation of chymase-positive cells in gastric cancer may lead to an increase of tumor angiogenesis, and may contribute to tumor growth and progression.

Significance of angiotensin II receptor blocker lipophilicities and their protective effect against vascular remodeling.

Although the lipophilicities of the various angiotensin II receptor blockers (ARBs) are very different, the relationship between lipophilicity and the protective effect against vascular remodeling is unclear. In this study, we compared the protective effects of a highly lipophilic ARB, telmisartan, and an ARB with low lipophilicity, losartan, on vascular function and oxidative stress in stroke-prone spontaneously hypertensive rats (SHR-SP). SHR-SP received oral placebo, 1 mg/kg telmisartan, or 10 mg/kg losartan for 2 weeks. The blood pressure (BP) in SHR-SP was significantly higher than that in Wistar-Kyoto (WKY) rats before treatment, and the BP was reduced equally in telmisartan- and losartan-treated SHR-SP compared to placebo-treated SHR-SP. Acetylcholine-induced vasorelaxation in isolated carotid arteries was significantly weaker in SHR-SP than in WKY rats, but in both telmisartan- and losartan-treated SHR-SP, acetylcholine-induced vasorelaxation was significantly higher than in placebo-treated SHR-SP. Moreover, acetylcholine-induced vasorelaxation in telmisartan-treated rats was significantly stronger than in losartan-treated SHR-SP. The expression of the endothelial nitric oxide synthase gene was significantly higher in telmisartan- and losartan-treated rats than in placebo-treated SHR-SP, and was significantly higher in telmisartan-treated rats than in losartan-treated rats. In contrast, the expression of the NAD(P)H oxidase subunit p22phox gene in telmisartan-treated SHR-SP was significantly lower than that in losartan-treated SHR-SP. Immunohistochemistry showed that angiotensin II expression in the aorta was significantly lower in telmisartan-treated SHR-SP than in losartan-treated SHR-SP. In conclusion, a highly lipophilic ARB, telmisartan, may be useful for preventing NAD(P)H oxidase activity, and thereby for conferring vascular protection.

Eplerenone inhibits atherosclerosis in nonhuman primates.

Aldosterone may be involved in the pathogenesis of atherosclerosis. We investigated the effect of eplerenone, a selective mineralocorticoid receptor blocker, on atherosclerosis in monkeys fed a high-cholesterol diet. Monkeys fed a high-cholesterol diet for 9 months were divided into 3 groups: those treated with a low dose of eplerenone (30 mg/kg per day); those treated with a high dose of eplerenone (60 mg/kg per day); and the placebo-treated group. The normal group consisted of monkeys fed a normal diet. There were no significant differences in blood pressure and cholesterol levels between the placebo- and eplerenone-treated groups. On the other hand, monocyte chemoattractant protein-1 and malondialdehyde-modified LDL were significantly higher in the placebo-treated group than in the normal group, whereas they were suppressed in the eplerenone-treated groups. The ratio of intimal volume to total volume by intravascular ultrasound analysis imaging of the aortas was dose-dependently lower in the eplerenone-treated groups than in the placebo-treated group. Acetylcholine-induced vasorelaxation was significantly weaker in the placebo-treated group than in the normal group, but the vasorelaxation was strengthened in the eplerenone-treated groups. A significant upregulation of angiotensin-converting enzyme activity was observed in the placebo-treated group, but the activity was suppressed in the eplerenone-treated groups. In conclusion, eplerenone may strengthen the endothelium-dependent relaxation and suppress angiotensin-converting enzyme activity in the vasculature, thus preventing the development of atherosclerosis in nonhuman primates.

Role of chymase-dependent angiotensin II formation in regulating blood pressure in spontaneously hypertensive rats.

Vascular smooth muscle cells in spontaneously hypertensive rats (SHR) express angiotensin II-forming chymase (rat vascular chymase [RVCH]), which may contribute to blood pressure regulation. In this study, we studied whether chymase-dependent angiotensin II formation contributes to the regulation of blood pressure in SHR. The systolic blood pressure in 16-week-old Wistar-Kyoto (WKY) rats was 113 +/- 9 mmHg, compared to 172 +/- 3 mmHg in SHR. Using synthetic substrates for measuring angiotensin-converting enzyme (ACE) and chymase activities, it was found that both ACE and chymase activities in extracts from SHR aortas were significantly higher than in those from WKY rat aortas. Using angiotensin I as a substrate, angiotensin II formation in SHR was found to be significantly higher than that in WKY rats, and its formation was completely suppressed by an ACE inhibitor, but not by a chymase inhibitor. RVCH mRNA expression could not be detected in aorta extracts from either WKY rats or SHR. In carotid arteries isolated from WKY rats and SHR, angiotensin I-induced vasoconstriction was completely suppressed by an ACE inhibitor, but not by a chymase inhibitor. Angiotensin I-induced pressor responses in both WKY rats and SHR were also completely inhibited by an ACE inhibitor, but they were not affected by a chymase inhibitor. In SHR, an ACE inhibitor and an angiotensin II receptor blocker showed equipotent hypotensive effects, but a chymase inhibitor did not have a hypotensive effect. These results indicated that chymase-dependent angiotensin II did not regulate blood pressure in SHR in the present study.

The regressive effect of an angiotensin II receptor blocker on formed fatty streaks in monkeys fed a high-cholesterol diet.

OBJECTIVES: To clarify the regressive effect of an angiotensin II type 1 receptor blocker (ARB) on already formed fatty streaks, we investigated the effect of the administration of an ARB, olmesartan, on formed fatty streaks in monkeys fed a high-cholesterol diet. METHODS: After the monkeys were fed a high-cholesterol diet for 6 months, intimal hyperplasia was clearly observed on intravascular ultrasound. For the next 6 months, the high-cholesterol diet was continued, and olmesartan (3 mg/kg per day) or placebo was administered. A control group was fed a normal diet for 12 months. RESULTS: Olmesartan did not significantly affect blood pressure or plasma cholesterol levels throughout the experiment. After 6 months of treatment with olmesartan, intimal hyperplasia was significantly lower than before treatment. Acetylcholine-induced relaxation in isolated carotid arteries was significantly less in the high-cholesterol diet placebo-treated group compared to the normal diet group, whereas its response was improved by olmesartan. Serum levels of monocyte chemoattractant protein were significantly increased with a high cholesterol load, but they were significantly suppressed by olmesartan. CONCLUSIONS: We have demonstrated for the first time that an ARB, olmesartan, was found to have a regressive effect on formed fatty streaks in monkeys.

The relationship of tryptase- and chymase-positive mast cells to angiogenesis in stage I non-small cell lung cancer.

OBJECTIVE: There are two types of human mast cells, tryptase-positive mast cells (MC(T)) and tryptase- and chymase-positive mast cells (MC(TC)). Although MC(T) have been reported to be related to the generation of angiogenesis, little is known about the involvement of MC(TC) in tumor angiogenesis. In this study, to clarify the relationship between MC(TC) and lung cancer angiogenesis, we evaluated MC(TC), MC(T), and microvessel counts in normal, border, and central lung cancer regions. METHODS: Tumor sections from 32 cases of adenocarcinoma and 13 cases of squamous cell carcinoma were immunostained for chymase to evaluate MC(TC), tryptase to evaluate MC(T,) and CD34 to evaluate microvessel counts. RESULTS: Both MC(TC) and MC(T) counts in the border lung cancer region were significantly higher than in the central region, and the MC(TC) and MC(T) counts in the central region were significantly higher than those in the normal regions. The microvessel counts in the border region were higher than those in the central region. The ratio of MC(TC) to MC(T) in the border region, but not in the central region, was significantly higher than that in the normal region. In the border region, significant correlations not only between MC(T) and microvessel count, but also between MC(TC) and microvessel count were observed. In the central region, a significant correlation between MC(TC) and the microvessel count was observed, but there was no significant correlation between MC(T) and the microvessel count. CONCLUSIONS: These findings suggest that MC(TC) may be involved in the pathogenesis of angiogenesis in lung cancer.

Effect of chymase inhibition on the arteriovenous fistula stenosis in dogs.

It was hypothesized that chymase may participate in hemodialysis vascular access dysfunction, as chymase has been known to be an effective enzyme in the conversion of angiotensin I (Ang I) to Ang II and in the latent TGF-beta1 to the active form. An arteriovenous (AV) fistula was created between the brachial artery and vein in dogs. In the AV anastomosis, when the walls of the venous and arterial sides were compared, the eccentric neointimal formation was most evident in the venous wall. Compared with the venous side downstream of the AV anastomosis, a severe neointimal hyperplasia was found in the venous side upstream of the AV anastomosis (intima/media, 153 +/- 25%). The chymase- and TGF-beta-positive mast cells were markedly accumulated in the proliferous neointima and media. In association with the reduction of chymase expression, a marked decrease in Ang II-, AT(1) receptor-, and TGF-beta-positive areas was achieved by NK3201 (a chymase inhibitor) treatment, and the neointima formation (intima/media: region A, 53 +/- 9%, P < 0.001; region B, 54 +/- 14%, P < 0.001) was also significantly suppressed in this group. Although lisinopril treatment also provided some beneficial effects with regard to the prevention of neointimal formation, the degree was less than that seen with chymase inhibition. These findings indicate that mast cell-derived chymase plays an essential role in the pathogenesis of the AV fistula access failure and that chymase inhibition may be a therapeutic target for the treatment of hemodialysis vascular access dysfunction in clinic settings.

Therapeutic applications of chymase inhibitors in cardiovascular diseases and fibrosis.

Chymase activates not only angiotensin I to angiotensin II but also latent transforming growth factor-beta-binding protein to transforming growth factor-beta. In dog grafted veins, chymase activity and angiotensin II concentration along with vascular proliferation were significantly increased, while they were significantly suppressed by a chymase inhibitor. After balloon injury in dog arteries, chymase activity was significantly increased in the injured artery, and a chymase inhibitor and an angiotensin AT(1) receptor antagonist were effective in preventing the vascular proliferation, but an angiotensin-converting enzyme inhibitor was ineffective. In fibrotic models, the tissue fibrosis was reduced by chymase inhibitors. In adhesion models, the transforming growth factor-beta concentration and adhesion formation were suppressed by chymase inhibitors. Therefore, chymase inhibitors may be useful for preventing cardiovascular diseases and fibrosis via inhibition of angiotensin II formation and transforming growth factor-beta activation.

Chymase as a novel target for the prevention of vascular diseases.

In vascular tissues, chymase catalyzes the production of angiotensin II, which plays a crucial role in vascular diseases. Recent clinical studies and animal models of vascular proliferation and atherosclerosis have provided evidence that angiotensin II formed by chymase is involved in these processes. These observations suggest that chymase might promote the development of vascular proliferation and atherosclerosis. Chymase also activates matrix metalloproteinase 9, which promotes aortic aneurysm and angiogenesis, and thus chymase inhibitors might also prevent the progression of abdominal aortic aneurysm and angiogenesis. We propose that chymase is a novel target for preventing vascular diseases.

Comparative effects of candesartan and amlodipine in a monkey atherosclerotic model.

Angiotensin II receptor blockers could prevent the development of atherosclerosis beyond reducing blood pressure in monkeys fed a high-cholesterol diet. However, it has been unclear whether hypotensive effects improve atherosclerosis in primates. We investigated whether antihypertensive agents, an angiotensin II receptor antagonist, candesartan, and a calcium channel blocker, amlodipine, prevent areas of atherosclerotic lesions in the aorta of monkeys fed a high-cholesterol diet. Seventeen male monkeys fed a high-cholesterol diet for 6 months were grouped as follows: a high-cholesterol diet group (n=5), a candesartan-treated group (1 mg/kg per day, n=6) and an amlodipine-treated group (5 mg/kg per day, n=6). Candesartan and amlodipine showed a similar hypotensive effect by decreasing the systolic blood pressure approximately 20 mmHg, while these agents did not affect serum cholesterol levels. The ratio of atherosclerotic area to total area in thoracic aorta was significantly decreased by treatment with candesartan, but the ratio tended to be decreased by treatment with amlodipine. Although the angiotensin-converting enzyme activity in plasma was not changed by treatment with candesartan or amlodipine, the angiotensin-converting enzyme activity in the thoracic aorta was obviously reduced by treatment with candesartan, but not with amlodipine. Therefore, a blockade of angiotensin II action rather than a hypotensive effect may play an important role in preventing the development of atherosclerosis in primates.