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Biomedical subjects

Johji Kato

Publications and source records attributed to Johji Kato.

At least 19 recordsLinked to original sources
PubMed2006

Isolation and identification of proangiotensin-12, a possible component of the renin-angiotensin system.

The renin-angiotensin (RA) system plays an important role in regulating blood pressure and fluid balance. In the search for bioactive peptides with an antibody binding to the N-terminal portion of angiotensin II (Ang II), we isolated a new angiotensinogen-derived peptide from the rat small intestine. Consisting of 12 amino acids, this peptide was termed proangiotensin-12 based on its possible role of an Ang II precursor. Proangiotensin-12 constricted aortic strips and, when infused intravenously, raised blood pressure in rats, while both the vasoconstrictor and pressor response to proangiotensin-12 were abolished by captopril and by CV-11974, an Ang II type I receptor blocker. Proangiotensin-12 is abundant in a wide range of organs and tissues including the small intestine, spleen, kidneys, and liver of rats. The identification of proangiotensin-12 suggests a processing cascade of the RA system, different from the cleavage of angiotensinogen to Ang I by renin.

Amino Acid Sequence↗
PubMed2006

Soluble guanylate cyclase stimulation on cardiovascular remodeling in angiotensin II-induced hypertensive rats.

It is unknown whether long-term pharmacological stimulation of soluble guanylate cyclase (sGC), elevating intracellular cGMP levels, has a beneficial effect on hypertension. The purpose of this study is to investigate the effects of BAY41-2272, an orally available sGC stimulator, on cardiovascular remodeling in hypertensive rats. Eight-week-old male Wistar rats with hypertension induced by angiotensin II infused subcutaneously at 250 ng/kg per minute were treated orally with a low ([L] 2 mg/kg per day) or high ([H] 10 mg/kg per day) dose of BAY41-2272 for 14 days. BAY41-2272-H partially suppressed the rise in blood pressure and reduced the heart weight (4.20+/-0.34 versus 3.68+/-0.20 mg/g; P<0.01), whereas BAY41-2272-L had no effect. However, both doses decreased the angiotensin II-induced left ventricular accumulation of collagen in the perivascular area (L, -20%, P<0.05; H, -30%, P<0.01) and myocardial interstitium (L, -21%, P<0.05; H, -38%, P<0.01), reducing the number of activated fibroblasts surrounding coronary arteries (L, -74%; H, -79%; P<0.05). BAY41-2272 downregulated the angiotensin II-induced left ventricular gene expression of type 1 collagen (L, -41%, P<0.05; H, -49%, P<0.01) and transforming growth factor-beta1 (L, -49%, P<0.05; H, -65%, P<0.01). cGMP levels were elevated by BAY41-2272 not only in the left ventricle, but also in cultured cardiac fibroblasts, resulting in reduced thymidine incorporation into the cells. Thus, stimulation of sGC by BAY41-2272 attenuates fibrosis of the left ventricle in rats with angiotensin II-induced hypertension partly in a pressure-independent manner, suggesting an important role for sGC generating cGMP in inhibiting cardiovascular remodeling.

Angiotensin II↗
PubMed2006

Adrenomedullin in mast cells of abdominal aortic aneurysm.

OBJECTIVES: Produced by vascular walls, adrenomedullin (AM) exerts antifibrotic actions in the process of cardiovascular remodeling. The purpose of this study was to examine the pathophysiological role of AM in the development of human abdominal aortic aneurysm (AAA). METHODS AND RESULTS: Immunohistochemical analyses revealed that vascular smooth muscle cells in the media were positive for AM in the early stage of atherosclerotic aorta. Intense immunoreactivity was observed in mast cells of the outer media and adventitia of AAA, and the number of mast cells was greater (p < 0.01) in AAA than in atherosclerotic aorta without any aneurysmal change. To determine the role of AM in mast cells, we examined cultured human mast cell leukemia line-1 (HMC-1) and fibroblasts isolated from AAA patients. Cultured HMC-1 cells were found to express preproAM gene and release AM peptide into the cultured media. When assessed by collagenase-sensitive [3H]proline incorporation and procollagen type I C-peptide secretion, collagen synthesis in co-culture of HMC-1 and the fibroblasts was reduced by 10(-6) mol/L synthetic AM, while conversely, it increased following blockade of the action of endogenous AM with 10 microg/mL anti-AM monoclonal antibody. CONCLUSION: The present study suggests an anti-fibrotic role for AM released from mast cells, providing new insight into the biological actions of mast cell-derived AM in the development of AAA.

Adrenomedullin↗
PubMed2005

Overexpression of proadrenomedullin N-terminal 20 peptide blunts blood pressure rise and attenuates myocardial hypertrophy and fibrosis in hypertensive rats.

We developed a transgenic (Tg) rat model that overexpresses human proadrenomedullin N-terminal 20 peptide (PAMP) only and then compared the effects of unilateral nephrectomy followed by a high salt diet for five weeks in Tg and wild-type rats. We found that systolic blood pressure was significantly lower in Tg UNX rats and cardiac hypertrophy and myocardial fibrosis was also attenuated in Tg rats. Evaluation of gene expression showed suppression of cardiac local renin-angiotensin system (RAS) in Tg rat. These results suggest that in addition to reducing blood pressure, PAMP suppresses cardiac hypertrophy through negative regulation of the local cardiac RAS.

Adrenomedullin↗
PubMed2005

Adrenomedullin: a protective factor for blood vessels.

Adrenomedullin (AM) is a vasodilator peptide having a wide range of biological actions such as reduction of oxidative stress and inhibition of endothelial cell apoptosis. The AM gene is expressed in vascular walls, and AM was found to be secreted from cultured vascular endothelial cells, smooth muscle cells, and adventitial fibroblasts. Plasma AM levels in patients with arteriosclerotic vascular diseases are elevated in possible association with the severity of the disease. When administered over a relatively short period, AM dilates blood vessels via an endothelium-dependent or independent mechanism. Experiments in vitro have shown that AM exerts multiple actions on cultured vascular cells, which are mostly protective or inhibitory against vascular damage and progression of arteriosclerosis. Either prolonged infusion or overexpression of AM suppressed intimal thickening, fatty streak formation, and perivascular hyperplasia in rodent models for vascular remodeling or atherosclerosis. Intimal thickening induced by periarterial cuff was more severe in AM gene-knockout mice than their littermates, suggesting a protective role for endogenous AM. Moreover, AM has recently been suggested to possess angiogenetic properties. Collectively, a body of evidence suggests that AM participates in the mechanism against progression of vascular damage and remodeling, thereby alleviating the ischemia of tissues and organs.

Adrenomedullin↗
PubMed2005

Beyond vasodilation: the antioxidant effect of adrenomedullin in Dahl salt-sensitive rat aorta.

We have investigated the antioxidant effect of adrenomedullin (AM) on endothelial function in the Dahl salt-sensitive (DS) rat hypertension model. Dahl salt-resistant (DR) and DS rats were fed an 8% NaCl diet. In addition, the DS rats were subcutaneously infused with either saline or recombinant human AM for 4 weeks. Although systolic blood pressures measured weekly in AM- and saline-infused rats did not significantly differ, aortic O2*- levels were significantly (P<0.01) higher in the latter. Likewise, both endothelial nitric oxide synthase (eNOS) mRNA and protein were significantly higher in saline-infused DS rats. Infusion of AM reduced both O2*- and eNOS expression to levels comparable to those seen in DR rats. AM infusion also upregulated the gene expression of guanosine-5'-triphosphate cyclohydrolase I and downregulated the expression of p22(phox), suggesting that AM increased the NOS coupling and bioavailability of NO. AM possesses significant antioxidant properties that improve endothelial function.

Adrenomedullin↗
PubMed2005

Effect of adrenomedullin administration on acetic acid-induced colitis in rats.

Adrenomedullin (AM) administered intracolonically ameliorated the severity of acetic acid-induced colonic ulceration in rats. Ulcers were induced by subserosal injection of acetic acid into the colon. AM-treated group was administered 0.25-1.0 microg of AM in 0.5 ml of saline intracolonically once a day; the control group received only saline. AM administration dose-dependently and significantly reduced the size of the ulcerative lesions, the associated edema, and the infiltration of the affected area by inflammatory cells. AM also reduced tissue levels of interleukin-6, but not interferon-gamma. AM reduces the severity of acetic acid-induced colitis in rats, probably by inhibiting the production and/or release of Th-2 cell-derived factors such as interleukin-6.

Acetic Acid↗
PubMed2005

Antifibrotic effect of adrenomedullin on coronary adventitia in angiotensin II-induced hypertensive rats.

OBJECTIVE: The extracellular matrix (ECM) determines the structural integrity of the heart and vasculature, participating in cardiovascular remodeling. We previously reported that adrenomedullin (AM) inhibited cellular proliferation and protein synthesis of cardiac fibroblasts; however, the precise mechanisms of AM actions as an antifibrotic factor remain unknown. The purpose of this study was to examine the biological actions of AM against the profibrotic factor angiotensin II (Ang II) in coronary adventitia. METHODS AND RESULTS: Rats with hypertension induced by Ang II infusion were administered 0.06 mug/kg/min recombinant human AM subcutaneously for 14 days. The AM infusion significantly (p<0.05) reduced the Ang II-induced increase of coronary adventitial fibroblasts expressing Ki-67 and alpha-smooth muscle actin (alpha-SMA) in the left ventricle, by 65%, and 62%, respectively, without affecting systolic blood pressure, left ventricle/body weight, or cross-sectional area of myocardial fibers. Collagen deposition of coronary arteries was reduced by the AM infusion (-24%, p<0.01), and these effects of AM were accompanied by significant reductions in gene expression of type 1 collagen (-49%, p<0.05) and transforming growth factor-beta1 (TGF-beta1) (-55%, p<0.01). In cultured cardiac fibroblasts, 10(-7) mol/L AM exerted an inhibitory effect on TGF-beta1-induced alpha-SMA expression (p<0.01) that was mimicked by 8-bromo-cAMP and attenuated by the protein kinase A inhibitor H-89. CONCLUSION: AM decreased Ang II-induced collagen deposition surrounding the coronary arteries, inhibiting myofibroblast differentiation and expressions of ECM-related genes in rats. The present findings further support the biological action of AM as an antifibrotic factor in vascular remodeling.

Actins↗
PubMed2005

Adrenomedullin alleviates not only neointimal formation but also perivascular hyperplasia following arterial injury in rats.

Producing components of the extracellular matrix, the vascular adventitia has been recognized as an important modulator of the vascular remodeling process, which determines the vessel architecture. In this study, we examined the effect of the vasodilator peptide adrenomedullin on vascular remodeling induced by balloon injury of rat carotid arteries. Endothelial denudation with wall stretch by ballooning not only induced neointimal formation accompanied with a reduced ratio of the lumen to vessel area, but also increased the fibroblast number and collagen deposition in the adventitial layer. When compared with the saline infusion, intravenous adrenomedullin infusion at 200 ng/h for 14 days suppressed the neointimal formation (-33%, P=0.033), reversing the ratio of lumen to vessel ratio (P=0.030), without affecting systolic blood pressure. Moreover, the adrenomedullin infusion decreased the number of adventitial fibroblasts (-41%, P<0.001) and the collagen deposition (-36%, P=0.006) in the adventitial layer of the injured artery. In conclusion, the intravenous adrenomedullin infusion effectively attenuates vascular remodeling following the arterial injury via suppression of hyperplasia in the intima and adventitia, suggesting a potential of adrenomedullin as a therapeutic tool against vascular remodeling.

Adrenomedullin↗
PubMed2005

Atrial and brain natriuretic peptides as markers of cardiac load and volume retention in primary aldosteronism.

BACKGROUND: Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones with natriuretic and vasodilator actions. The present study was carried out to determine the natriuretic peptide that is closely related to cardiac load and volume retention in patients with primary aldosteronism (PA). METHODS: We examined 11 patients with PA due to aldosterone-producing adrenal adenoma before and after surgical resection. Plasma levels of ANP and BNP were measured by specific immunoradiometric assays, and total blood volume was determined by a plasma tracer method with (131)I-human albumin. RESULTS: Plasma levels of ANP and BNP were elevated in the PA patients compared with normotensive control subjects (P < .01), and the elevated ANP and BNP levels were reduced (P < .01) after adenoma resection. When analyzed with the pre- and postoperative data, a significant relationship was observed between mean blood pressure and plasma levels of ANP (r = 0.64, P < .01) and BNP (r = 0.58, P < .01). The BNP was significantly correlated with the SV1 + RV5 voltage (r = 0.65, P < .01) and with total blood volume (r = 0.57, P < .01), but this was not the case for ANP. CONCLUSION: The present results suggest that the plasma level of BNP is more closely related to cardiac load or volume status than ANP is, in patients with PA due to adrenal adenoma.

Adenoma↗
PubMed2004

Adrenomedullin induces matrix metalloproteinase-2 activity in rat aortic adventitial fibroblasts.

BACKGROUND: The delicate balance of the extracellular matrix (ECM) determines the stiffness of the vascular wall, and adventitial fibroblasts are involved in ECM formation by synthesizing and degrading matrix proteins. In the present study, we examined the effect of the bioactive peptide adrenomedullin (AM) on activity and expression of matrix metalloproteinases (MMPs) in cultured aortic adventitial fibroblasts. METHODS AND RESULTS: In cultured adventitial fibroblasts isolated from aorta of adult Wistar rats, 10(-6)mol/L angiotensin II (Ang II) significantly (p<0.05) down-regulated MMP-2 activity as determined by in vitro gelatin zymography. In contrast, 10(-7)mol/L synthetic rat AM significantly (p<0.05) stimulated zymographic MMP-2 activity by 23%, increasing intracellular cAMP, and AM abolished the action of Ang II, augmenting the MMP-2 activity. Similarly, Ang II down-regulated MMP-2 protein expression assessed by Western blotting, whereas AM increased it. Furthermore, 8-bromo-cAMP, an analogue of cAMP, mimicked the effect of AM, and H-89, an inhibitor for protein kinase A (PKA), significantly decreased the basal and AM-induced MMP-2 activity. CONCLUSION: This study provides a new insight into the biological action of AM and its intracellular signaling system of cAMP/PKA stimulating the matrix degrading enzyme MMP-2, suggesting an important role for this molecule in modulating ECM deposition in the adventitial layer.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2004

Adrenomedullin administration immediately after myocardial infarction ameliorates progression of heart failure in rats.

BACKGROUND: Adrenomedullin (AM) is expressed in cardiac tissue, and plasma AM levels increase in patients with acute myocardial infarction (MI). This study was performed to determine whether AM administration immediately after acute MI inhibits progression of heart failure in rats. METHODS AND RESULTS: Rats were infused with 1.0 microg/h IP AM or saline over 7 days immediately after MI inducted by left coronary ligation and were examined 9 weeks after MI. Compared with the saline infusion, AM infusion significantly improved survival (59% versus 81%; P<0.05) and body weight gain (32%; P<0.01) and reduced heart weight (-28%; P<0.01), lung weight (-26%; P<0.01), left ventricular (LV) end-diastolic pressure (11.4+/-2.0 versus 4.0+/-0.6 mm Hg, mean+/- SEM; P<0.01), collagen volume fraction of noninfarcted LV (-39%; P<0.05), and plasma levels of endogenous rat AM (-38%; P<0.05) without affecting infarct size. To investigate the mechanism of AM actions, another series of MI rats infused with AM were killed on day 7. AM infusion had no effect on organ weights and hemodynamic parameters on day 7 of MI but significantly reduced urinary excretion of isoprostane (-61%; P<0.01) and noninfarcted LV mRNA levels of ACE (-31%; P<0.05) and p22-phox (-30%; P<0.05). CONCLUSIONS: AM administration during the early period of MI improved the survival and ameliorated progression of LV remodeling and heart failure. This beneficial effect was accompanied by reductions in oxidative stress and ACE mRNA expression in noninfarcted LV in the AM infusion period.

Adrenomedullin↗
PubMed2004

Development of an ultrasensitive enzyme immunoassay for human proadrenomedullin N-terminal 20 peptide and direct measurement of two molecular forms of PAMP in plasma from healthy subjects and patients with cardiovascular disease.

OBJECTIVE: Proadrenomedullin N-terminal 20 peptide (PAMP) processed from an adrenomedullin precursor is a potent hypotensive peptide. It was anticipated that a mature form of PAMP (m-PAMP) and an intermediate PAMP-gly existed together in the blood. To measure concentrations of PAMPs in human plasma directly, we have developed a highly sensitive enzyme immunoassay (immune complex transfer enzyme immunoassay, ICT-EIA). DESIGN AND METHODS: PAMP was reacted simultaneously with 2,4-dinitrophenyl (DNP)-biotinyl-bovine serum albumin (BSA)-anti-PAMP Fab' conjugate and anti-PAMP Fab'-beta-D-galactosidase conjugate. The immune complex that was formed was initially trapped onto a polystyrene bead coated with anti-DNP IgG, and then transferred onto a second polystyrene bead coated with streptavidin. The resulting three-component complex was then assayed fluorometrically. RESULTS: The detection limits of ICT-EIA for both m-PAMP and PAMP-gly were 0.1 pmol/l with as little as 10 microl of plasma, and were a hundred times higher than with conventional radioimmunoassay (RIA). Using ICT-EIA, we determined that the plasma concentrations of m-PAMP and PAMP-gly in 51 healthy volunteers were 0.51 +/- 0.19 and 1.15 +/- 0.38 pmol/l (mean +/- SD), respectively. Both plasma m-PAMP and PAMP-gly concentrations in patients with a variety of diseases, including hypertension, heart failure, chronic renal failure, and hemodialysis, were significantly higher than those in healthy subjects. In addition, both plasma m-PAMP and PAMP-gly concentrations in patients with New York Heart Association (NYHA) class I-IV heart failure were increased in proportion to clinical severity. CONCLUSIONS: These sensitive and specific ICT-EIAs may be used as a powerful tool for investigating the cardiovascular system in patients with heart failure.

Adrenomedullin↗
PubMed2003

Angiotensin II modulates gene expression of adrenomedullin receptor components in rat cardiomyocytes.

Both adrenomedullin (AM) and angiotensin II (Ang II) are locally-acting hormones in the cardiac ventricles. Previously we reported that AM inhibits Ang II-induced hypertrophy of cultured rat neonatal cardiomyocytes. In this study, we examined whether Ang II affects the gene expression of the AM receptor components of calcitonin-receptor-like receptor (CRLR) and receptor-activity-modifying protein (RAMP) in rat cardiomyocytes. The mRNA levels of RAMP1 and RAMP3 were significantly elevated following 24-h treatment with Ang II without a change of those of RAMP2 and CRLR. AM increased the intracellular cAMP level and the cAMP accumulation by AM was significantly amplified by the 24-h preincubation with Ang II. The effects of Ang II on RAMP1 and RAMP3 expression were abolished by an Ang II type 1 (AT1) receptor antagonist, but not by an AT2 receptor antagonist. Thus, Ang II modulates gene expression of the AM receptor components via AT1 receptor, suggesting alteration of AM actions by Ang II in cultured rat cardiomyocytes.

Angiotensin II↗