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K T Weber

Publications and source records attributed to K T Weber.

At least 91 records · Page 5Linked to original sources
PubMed1996

Valvular interstitial cells express angiotensinogen and cathepsin D, and generate angiotensin peptides.

Cells capable of de novo angiotensin (Ang)II generation in the heart remain unidentified. High-density angiotensin converting enzyme (ACE) binding has been localized to sites of high collagen turnover, such as heart valve leaflets and their valvular interstitial cells (VIC). VIC express ACE mRNA and their membrane-bound ACE utilizes AngI as substrate. Whether VIC also express angiotensinogen (Ao) and an aspartyl protease, and whether they generate AngI and II de novo, is presently unknown. We sought to address these questions in serum-deprived cultured VIC. Ao, renin and cathepsin D (Cat-D) mRNA expression was addressed by RT-PCR. Production of Ao, AngI and AngII peptides were measured in VIC-culture media by radioimmunoassay (RIA). Immunoreactive Cat-D was detected by immunofluorescein labeling and Western blotting. Cat-D and renin activities were determined by spectrofluorometric and autoradiographic methods and AngI generation by RIA. Results showed (a) expression of Ao and Cat-D both at mRNA and protein levels; (b) AngI and AngII peptides in culture media; (c) acceleration of AngII production by exogenous AngI (1 nmol/l), which was blocked by lisinopril (0.1 mumol/l); (d) that dexamethasone (0.1 mumol/l) increased AngII production; (e) a 46 kDa immunoreactive Cat-D protein by Western blotting; (f) aspartyl protease activity, using chromogenic and 125I-labeled Ao as substrates, inhibited by pepstatin-A; and (g) the absence of renin mRNA and activity. It is concluded that at both the mRNA and protein levels, cultured VIC express Ao and Cat-D, and can generate AngI and AngII peptides by the action of a non-renin protease Cat-D and ACE, respectively. VIC therefore appear to represent a constitutive nonendothelial cell found in adult rat heart valve leaflets, which are capable of de novo Ang peptide generation.

Angiotensin I↗
PubMed1996

Angiotensin-converting enzyme and wound healing in diverse tissues of the rat.

Autoradiographic binding density of angiotensin-converting enzyme (ACE), an indirect measure of ACE activity, is markedly increased at sites of fibrous tissue that appear in the injured heart. This includes myocardial infarction (MI) caused by left coronary artery ligation; endocardial fibrosis of the interventricular septum and perivascular fibrosis of intramyocardial coronary arterioles of the right ventricle, each of which appear remote to MI; and pericardial fibrosis after pericardiotomy (without MI). Expressed in fibroblast-like cells found at each site of tissue repair, ACE may be common to tissue repair in the rat heart, irrespective of the etiologic basis of injury. To address this hypothesis and to determine whether this also applies to other tissues (skin and kidney), the present study was undertaken. ACE binding density was measured by quantitative in vitro autoradiography (125I-351A) in injured rat heart, skin, and kidney. Experimental observations included foreign-body fibrosis after placement of silk ligature in skin or myocardium, endomyocardial myocyte necrosis and fibrosis that accompanied isoproterenol administration (1 mg/kg sc x 2 days), and embolic infarction of the kidney as a result of mural thrombus of the left ventricle that appeared after anterior MI. Fibrosis was identified by collagen-specific staining with picrosirius red. Hematoxylin-eosin staining and immunohistochemical labeling with alpha-smooth muscle actin (alpha-SMA) antibody were used to address cell morphology and phenotype, respectively. We found (1) endomyocardial fibrosis 2 weeks after isoproterenol; (2) fibrosis surrounding silk suture in heart and skin 1 week after placement; (3) renal infarction 1 week after left coronary artery ligation; (4) numerous fibroblast-like cells containing alpha-SMA, as well as macrophages, at sites of repair in all tissues studied; and (5) markedly increased ACE binding density at each of these sites. Thus ACE is integral to tissue repair in the heart, skin, and kidney of the rat, irrespective of the etiologic basis of injury. At these sites ACE may serve to regulate local concentrations of substances involved in tissue repair.

Animals↗
PubMed1996

Advanced hypertensive heart disease in spontaneously hypertensive rats. Lisinopril-mediated regression of myocardial fibrosis.

Left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHR) is accompanied by a structural remodeling of the myocardium that includes myocyte hypertrophy and interstitial and perivascular fibrosis of intramyocardial coronary arteries. The structural abnormalities related to fibrous tissue accumulation lead to increased myocardial diastolic stiffness and ultimately impaired systolic function of the left ventricle. It has been shown in 14-week-old SHR with early hypertensive heart disease that myocardial fibrosis could be reversed and myocardial diastolic stiffness normalized by 12-week treatment with the angiotensin-converting enzyme inhibitor lisinopril. Whether such functional defects of the myocardium, based on adverse structural changes, are also reversible in advanced hypertensive heart disease has been questioned. Therefore, we treated 78-week-old male SHR that had chronic hypertension and advanced LVH with severe myocardial fibrosis and age- and sex-matched normotensive Wistar-Kyoto rats (WKY) with 20 mg/kg per day oral lisinopril for 8 months. Compared with untreated SHR or WKY, we found the following: (1) Systolic arterial pressure was normalized (P < .025) and LVH completely reversed (P < .025) in SHR, with no significant reduction in systolic arterial pressure or left ventricular mass in WKY; (2) morphometrically determined myocardial fibrosis in SHR was significantly reversed (P < .025) and associated with improved diastolic stiffness (P < .05), which was measured in the isolated heart by calculation of the stiffness constant of the myocardium; no significant changes occurred in WKY; (3) reversal of myocardial fibrosis was accompanied by an increase (P < .025) in myocardial matrix metalloproteinase 1 activity determined by degradation of [14C]collagen with myocardial tissue extracts after trypsin activation of myocardial promatrix metalloproteinase 1; matrix metalloproteinase 1 activity remained unchanged in WKY treated with lisinopril; and (4) systolic dysfunction, measured by a significantly (P < .025) diminished slope of the systolic stress-strain relation under isovolumic conditions of the left ventricle, was found in 110-week-old SHR, and it could be prevented by lisinopril treatment. Thus, long-term angiotensin-converting enzyme inhibition with lisinopril normalized arterial pressure and LVH, reversed myocardial fibrosis, and improved abnormal myocardial diastolic stiffness in advanced hypertensive heart disease in SHR. In addition, systolic dysfunction of the left ventricle could be prevented. The fibrolytic response to lisinopril was at least partly due to enhanced collagen degradation by activation of tissue matrix metalloproteinase 1.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Cells expressing angiotensin II receptors in fibrous tissue of rat heart.

OBJECTIVE: Following left coronary artery ligation, markedly increased angiotensin II (AngII) receptor binding appears at the site of myocardial infarction (MI). This is also true for the fibrosed visceral pericardium in rats following pericardiotomy (with or without MI). Cells expressing AngII receptors at these sites remain unknown. In the present study, we sought to identify cells expressing AngII receptors at these sites of fibrosis in the rat heart during both early and late stages of wound healing. METHODS: MI was created by left coronary artery ligation. Sham operation included thoracotomy, pericardiotomy and placement of silk ligature around the left coronary artery without MI. Hearts were collected at postoperative week 1 and 4. In serial sections: autoradiography (125I[Sar1,Ile8]AngII) was used to determine cells expressing AngII receptors; hematoxylin-eosin and alpha smooth muscle actin were used for identification of cell morphology and phenotype, respectively; and picrosirius red for identification of fibrillar collagen. RESULTS: (1) at week 1, necrotic tissue at the site of MI was surrounded by granulation tissue that included macrophages, alpha smooth muscle actin fibroblast-like cells, or myofibroblasts, fibrillar collagen, and new vessels; (2) at week 4, scar tissue had formed and remaining cells were primarily myofibroblasts; (3) pericardial fibrosis was evident at weeks 1 and 4 and contained myofibroblasts, not macrophages or new vessels; (4) at week 1 and 4 myofibroblasts were the predominant cell expressing high-density AngII receptors at the site of MI, while fibroblasts, macrophages and vessels demonstrated low-density AngII receptor binding; and (5) at weeks 1 and 4, myofibroblasts express high-density AngII receptor binding in pericardial fibrosis. CONCLUSION: In a rat model of tissue repair involving either MI or pericardial fibrosis, increased AngII receptor expression is primarily associated with myofibroblasts. This suggests AngII may play a role in mediating the fibrogenic response provided by this wound healing cell at sites of tissue injury in the rat heart.

Angiotensin II↗
PubMed1996

Angiotensin II-induced myocardial fibrosis in rats: role of nitric oxide, prostaglandins and bradykinin.

OBJECTIVE: Chronic elevations in plasma angiotensin II (AngII) are associated with an efflux of plasma macromolecules into the perivascular and contiguous interstitial space. This is followed by the appearance of macrophages and type I collagen-producing, fibroblast-like cells that precede the accumulation of fibrous tissue at these sites. Whether this perivascular and interstitial fibrosis is a direct effect of AngII on collagen turnover of these cells or an indirect response mediated by nitric oxide, prostaglandins and/or bradykinin released in response to AngII, is uncertain. METHODS: We measured perivascular and interstitial fibrosis (picrosirius-stained tissue) in response to 14-day infusion of AngII (150 ng/kg/min, s.c.) in male Sprague-Dawley rats. Treated animals were compared to untreated controls and to groups receiving AngII together with either an NO-synthase inhibitor [NG-nitro-L-arginine methyl ester (L-NAME) 10 mg/kg/day in drinking water], a cyclo-oxygenase inhibitor (indomethacin, 2 mg/kg/day in drinking water), or a bradykinin B2 receptor antagonist (Hoe140, 115 ng/kg/min, s.c.). RESULTS: When left and right ventricles of treated rats were compared to untreated controls, AngII led to a respective 68 and 48% increase in perivascular collagen volume fraction (PCVF) and a 54 and 22% increase in interstitial collagen volume fraction (ICVF). Co-administration of AngII + L-NAME did not attenuate either PCVF or ICVF while indomethacin significantly attenuated PCVF by 37 and 33% of left and right ventricle, respectively, but did not alter ICVF in either ventricle when compared to AngII-treated animals. Co-administration of AngII + Hoe140 completely prevented perivascular and interstitial collagen accumulation with the extent of perivascular fibrosis comparable to untreated controls. CONCLUSION: The perivascular and interstitial fibrosis of the rat right and left ventricles seen in association with the exogenous administration of AngII is mediated by the release of bradykinin and prostaglandins, and therefore is an indirect response to elevated circulating AngII.

Angiotensin II↗
PubMed1995

Role of angiotensin II and prostaglandin E2 in regulating cardiac fibroblast collagen turnover.

In hypertensive heart disease, after myocardial infarction or in congestive heart failure, myocardial fibrosis presenting as a diffuse perivascular and interstitial accumulation of fibrillar collagens within the normal connective tissue structures of the myocardium is associated with an activated renin-angiotensin system (RAS). This reactive fibrosis occurs in the overloaded left ventricle and the nonoverloaded right ventricle irrespective of myocyte necrosis or the development of myocyte hypertrophy. Therefore, it appears that hemodynamic factors or the load of the ventricle are not primarily responsible for the adverse fibrous tissue response in the myocardium, and humoral factors may play a key role in regulating the myocardial collagen matrix. The neurohumoral response in hypertensive heart disease, after myocardial infarction with overall deterioration of left ventricular function or congestive heart failure leads to an activation of either the cardiac or the circulating RAS, which closely interacts with the bradykinin-prostaglandin system. To ascertain whether the RAS modulates collagen fibroblasts that express mRNAs for types I and III collagens (the major fibrillar collagens in the heart) and matrix metalloproteinase 1 (MMP1; the key enzyme for collagen degradation), collagen synthesis was measured by [3H]proline incorporation normalized to total protein synthesis and MMP1 activity was determined by degradation of [14C]collagen in cultured fibroblasts after 24-hour incubation with various concentrations of angiotensin II or PGE2 (10(-11)-10(-3) M) under serum-free conditions. In addition, effects of angiotensin II were evaluated in the presence or absence of either type 1 (ICI D8731) or type 2 (PD 123177) angiotensin II (AT1 or PGE2 (10(-11)-10(-3) M) under serum-free conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗