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K T Weber

Publications and source records attributed to K T Weber.

At least 109 records · Page 6Linked to original sources
PubMed1995

Connective tissue and repair in the heart. Potential regulatory mechanisms.

The heart is composed of highly differentiated cardiac myocytes, which constitute parenchyma, and stroma or connective tissue. Fibrillar collagen turnover in the heart and its valve leaflets, in particular, is dynamic and essential to tissue repair. Emerging evidence further suggests connective tissue is a metabolically active entity, where peptide hormones are generated and degraded and, in turn, these peptides regulate collagen turnover. This concept arose from quantitative in vitro autoradiography using an iodinated derivative of lisinopril (125I-351A) as ligand to localize angiotensin converting enzyme (ACE) binding density within the heart. A heterogeneous distribution was found: low-density ACE binding within atria and ventricles; high ACE binding density at sites of high collagen turnover, such as valve leaflets, adventitia, and fibrous tissue of diverse etiologic origins. ACE-producing cells at these latter sites were identified by monoclonal ACE antibody. They included valvular interstitial cells (VIC) and fibroblast-like cells each of which also contained alpha-smooth muscle actin and the transcript for type I collagen (in situ hybridization). Substrate utilization in cultured VIC was found to include angiotensin I and bradykinin. Angiotensin II and bradykinin receptor-ligand binding was observed in VIC and at fibrous tissue sites. Connective tissue ACE is independent of circulating angiotensin II. In vivo, fibrous tissue formation is attenuated by ACE inhibition or antagonism of AT1 receptor. Angiotensin II and bradykinin are stimulatory and inhibitory, respectively, to cultured adult cardiac fibroblast collagen synthesis suggesting a paradigm of reciprocal regulation to fibroblast collagen turnover. Stroma and its cellular constituents represent a dynamic metabolic entity that regulates its own peptide hormone composition and turnover of fibrillar collagen. These findings may provide insights that could be used to advantage to either promote or forestall fibrous tissue formation depending on the nature of cardiovascular disease.

Angiotensin I↗
PubMed1995

Heart failure: lessons learned over the past 25 years.

Over the past 25 years, a great deal has been learned about the pathophysiology and management of heart failure--a major health problem whose prevalence and incidence have not declined, unlike other cardiovascular disorders. Several of these lessons are reviewed herein. However, despite these advances, important issues remain to challenge both the practicing physician and the research scientist.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Bradykinin receptor and tissue ACE binding in myocardial fibrosis: response to chronic angiotensin II or aldosterone administration in rats.

High density angiotensin converting enzyme (ACE) binding is present in the perivascular fibrosis involving intramyocardial coronary arteries and the microscopic scarring of the myocardium that accompanies chronic elevations in circulating angiotensin II (AngII) and/or aldosterone (ALDO). As a kininase II, ACE degrades bradykinin. Herein we sought to determine whether bradykinin (BK) receptor binding was associated with ACE binding in each of these experimental models. BK receptor binding was localized and quantified by in vitro quantitative autoradiography, using [125I-Tyr8]BK. In serial sections of the same heart hematoxylin and eosin (H&E) and picrosirius red (PSR) staining were utilized to address cardiac myocyte injury and fibrosis, respectively. Four experimental groups were examined: unoperated, untreated, age/sex matched controls: age/sex matched uninephrectomized control rats receiving a high sodium diet; animals that received AngII (9 micrograms/h sc) for 2, 4 or 6 weeks; and uninephrectomized rats on a high sodium diet that received ALDO (0.75 micrograms/h sc) for similar periods of time. We found: (a) myocardial fibrosis, including perivascular fibrosis and microscopic scarring, at week 2 of AngII, but not until week 4 or more of ALDO treatment; (b) low BK receptor binding in normal ventricles that was increased in scars and markedly increased in perivascular fibrosis at week 2 of AngII and each increased further at week 4 and 6 of AngII: (c) low BK receptor binding at week 2 and 4 weeks of ALDO treatment which became markedly increased at fibrous tissue sites at week 6. BK receptor and ACE binding were anatomically coincident and localized to each site of fibrosis in both models. The co-location of BK receptor and ACE binding in these models raises the prospect that fibrous tissue ACE may utilize BK as substrate and BK, in turn, may play a role in fibrous tissue formation.

Aldosterone↗
PubMed1995

Chronic mineralocorticoid excess and cardiovascular remodeling.

Chronic mineralocorticoid (MC) excess, whether due to elevated plasma aldosterone (ALDO) or deoxycorticosterone (DOC), is associated with a perivascular fibrosis of systemic and coronary arterioles. This remodeling of resistance vessels contributes to the appearance of hypertension. Chronic MC excess is also accompanied by cardiac myocyte necrosis, secondary to myocardial potassium depletion, and a subsequent reparative fibrosis that appears in the normotensive, nonhypertrophied right and hypertensive, hypertrophied left ventricles. Fibrosis contributes to the appearance of ventricular arrhythmias and dysfunction. Herein, clinical and experimental evidence linking chronic, inappropriate (relative to dietary sodium) elevations in circulating ALDO and DOC with these reactive and reparative forms of fibrous tissue formation in the heart and other tissues is presented.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Regulation of collagen degradation in the rat myocardium after infarction.

Fibrillar collagens, essential for maintaining the structural integrity of the myocardium, are degraded by matrix metalloproteinase (MMP-1). In other tissues collagenolysis is an important component of wound healing. Here we examined collagen degradation in the myocardium after infarction. Collagenase activity, measured by zymography, and expression of matrix metalloproteinase (MMP-1) and tissue inhibitor of metalloproteinase (TIMP) mRNA, detected by Northern blotting and in situ hybridization, in the rat heart 6 h to 28 days after left coronary artery ligation were studied. Sham-operated rats served as controls. Infarcted left ventricle was compared to non-infarcted right ventricle and interventricular septum and to sham-operated tissues. We found a transient increase in collagenase activity in the infarcted left ventricle, which began at day 2 (4.5-fold increase compared to controls), peaked at day seven (6.5-fold increase) and declined thereafter, together with a concomitant increase and contribution in collagenolytic activity of gelatinases (MMP-2 and MMP-9). An increase in collagenase mRNA was not seen until day 7 and only in the infarcted ventricle, while changes in MMP-1 activity or mRNA expression were not observed at remote sites or in sham-operated controls. Transcription of TIMP mRNA was observed at 6 h (two-fold increase) in the infarcted ventricle, peaked on day two after MI (eight-fold increase) and slowly decreased thereafter. No change in TIMP mRNA expression was observed at remote sites or in sham-operated controls. Cells responsible for transcription of MMP-1 and TIMP mRNA were fibroblast-like cells, not inflammatory or endothelial cells. At the site of infarction post-translational activation of latent collagenase (MMP-1) plays a greater role in the wound healing response than transcription of collagenase mRNA. Collagenase mRNA is synthesized when the latent extracellular pool of MMP-1 is reduced through the activation of latent collagenases and gelatinases. TIMP mRNA synthesis is regulated by the activation of MMPs with the balance between collagenase activation and TIMP inhibition determining the amount of collagenolysis in infarcted tissue.

Animals↗
PubMed1995

Connective tissue: a metabolic entity? .

The heart is composed of parenchyma (cardiac myocytes) and stroma (connective tissue). Stroma is presumed inert and therefore little attention has been paid to its regulation. Contrary to this notion, evidence presented here raises the possibility that connective tissue is a metabolically active entity capable of regulating peptide hormone generation and degradation and these hormones, in an autocrine manner, regulate collagen turnover. This concept has evolved from quantitative in vitro autoradiography (using 125I-351A), which localized angiotensin converting enzyme (ACE) binding density within the heart. A heterogenous distribution was found. Low-density ACE is present within atria and ventricles. At sites of high collagen turnover, such as valve leaflets, adventitia and fibrous tissue of diverse etiologic origins. ACE binding density is high and independent of circulating angiotensin II. ACE-producing cells at these sites, identified by monoclonal ACE antibody and 125I-351A binding, include fibroblast-like alpha actin-containing cells that express the transcript for type I collagen (in situ hybridization). Receptor-ligand binding for angiotensin II and bradykinin is found in fibrous tissue, where these peptides may provide for a reciprocal regulation of fibroblast collagen turnover. Connective tissue formation is attenuated by ACE inhibition or antagonism of type I angiotensin II receptor. Thus, emerging evidence raises the possibility that stroma and its cellular constituents is a dynamic, metabolically active entity regulating its own peptide hormone composition and, in turn, its turnover of fibrillar collagen.

Animals↗
PubMed1995

Temporal differences in fibroblast proliferation and phenotype expression in response to chronic administration of angiotensin II or aldosterone.

Chronic activation of the circulating renin-angiotensin-aldosterone system (RAAS), as can occur with unilateral renal ischemia (URI), is associated with an adverse structural remodeling of the right and left ventricles characterized by reparative (i.e., microscopic scars) and reactive (i.e., perivascular/interstitial) fibrosis. The time course and cells involved in fibroplastic and fibrogenic phases of these events are unclear. Hearts were examined over the course of 8 weeks in rats infused with either angiotensin II or aldosterone, and compared to rats with URI. Tissue sections from the same heart were stained with hematoxylin and eosin, collagen specific picrosirius red, or immunolabeled with PCNA or alpha smooth muscle actin antibody. With angiotensin II or renal ischemia, fibroblast proliferation, presenting as focal accumulations at both sites of myocyte necrosis and widespread perivascular locations, was present in each ventricle on days 2 and 4, but not thereafter, alpha-Smooth muscle actin containing cells (myofibroblasts) appeared at day 2 and persisted through week 2 with renal ischemia and week 6 with angiotensin II. Macrophages, neutrophils and lymphocytes were transiently found at sites of necrosis between day 2-4 of renal ischemia. AngII-induced necrotic sites were characterized by macrophages and lymphocytes from day 2 through week 6, and neutrophils at day 2-4. Increased collagen volume fraction, presenting as immature scars associated with fibroblast clusters and interstitial/perivascular fibrosis, was evident on day 14 in both ventricles. In contrast, fibroblast proliferation during aldosterone infusion did not appear in both ventricles until week 3 and was associated with a subsequent reparative and reactive fibrosis as early as 4 weeks. Myofibroblasts became evident between 3-6 weeks; macrophages and lymphocytes were seen between 3-8 weeks. Neutrophils were not seen at any time point with aldosterone. Thus, the temporal cellular response and appearance of myocardial fibrosis associated with chronic elevations in angiotensin II and/or aldosterone differ. We conclude that separate pathogenic mechanisms are operative with these effector hormones of the RAAS.

Actins↗
PubMed1995

Myocardial fibrosis in hypertensive heart disease: an overview of potential regulatory mechanisms.

Myocardial fibrosis in hypertensive heart disease (HHD) can present as a reactive process, involving intramyocardial coronary arteries and arterioles with extensions of collagen into the neighbouring interstitial space, and as a replacement for necrotic cardiac myocytes. Fibrosis adversely affects myocardial stiffness and therefore regulatory mechanisms are of considerable interest. Mechanisms responsible for scarring (reparative fibrosis) are based on factors that adversely influence myocyte survival. This topic is not covered in this brief review. Mechanisms responsible for the perivascular/interstitial fibrosis that appear in both the normotensive, non-hypertrophied right and the pressure overloaded, hypertrophied left ventricule in HHD are addressed herein. They include: (a) angiotensin II (Ang II)-mediated coronary vascular hyperpermeability with subsequent fibrosis; (b) direct hormonal regulation of fibroblast collagen turnover, whereby Ang II, aldosterone and/or endothelins may be involved; (c) autocrine and paracrine signalling between fibroblasts and/or endothelial cells that alters collagen synthesis and degradation and which includes an angiotensin converting enzyme found in fibrous tissue. Collagen turnover in the myocardium is a dynamic process and fibrous tissue is anything but inert.

Animals↗
PubMed1995

Hormonal regulation of cardiac fibroblast function.

In arterial hypertension or congestive heart failure, myocardial fibrosis is associated with an activated renin-angiotensin-aldosterone system (RAAS). This reactive fibrosis presents as an excessive accumulation of fibrillar collagen within the normal connective tissue structures of the myocardium in either ventricle, irrespective of its haemodynamic load. It therefore would appear that circulating (hormonal) and not haemodynamic factors are responsible for this adverse fibrous tissue response. The cardiac fibroblast expresses mRNA for types I and III collagens, the major fibrillar collagens in the heart, and for collagenase or matrix metalloproteinase 1 (MMP 1), the key enzyme for interstitial collagen degradation. Therefore, adult rat cardiac fibroblasts were cultured to ascertain whether the RAAS effector hormones angiotensin II (Ang II) or aldosterone (Aldo) directly stimulate collagen synthesis or inhibit MMP 1 production. Collagen synthesis, determined by 3H-proline incorporation and MMP 1 activity determined by degradation of 14C-collagen, were measured under serum-free conditions in confluent, quiescent fibroblasts after 24 h incubation with Ang II or Aldo over a wide range of concentrations (10(-11) -10(-6) M). In addition, collagen synthesis was measured after incubation with the mineralocorticoid, dexoycorticosterone (DOC), or the prostaglandin, PGE2. Collagen synthesis, normalized per total protein synthesis, increased significantly in a dose-dependent manner after incubation with either mineralocorticoid hormone, Aldo or DOC, or after incubation with Ang II compared with untreated control cells. In contrast, collagen synthesis was significantly decreased with PGE2 treatment. This increase in collagen synthesis in Ang II or mineralocorticoid-stimulated fibroblasts could be completely abolished by Ang II type 1 or mineralocorticoid receptor antagonists, respectively. (ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Structural remodelling of the heart by fibrous tissue: role of circulating hormones and locally produced peptides.

Symptomatic heart failure is accompanied by diastolic ventricular dysfunction due largely to an extensive reactive and reparative fibrosis. Experimental evidence suggests a clear association between myocardial fibrosis and chronic inappropriate elevations in circulating angiotensin II (Ang II) and/or aldosterone. Although not entirely elucidated, injury follows Ang II-associated release of adrenal medullary catecholamines and aldosterone-induced myocardial potassium depletion. Increasing evidence indicates locally produced cardiac Ang II plays an important role in tissue repair that may underlie myocardial remodelling, the fibrous tissue accumulation both at and remote to the site of myocardial infarction (MI). Angiotensin converting enzyme (ACE) binding density markedly increases at these fibrous tissue sites after experimental MI, indicating an involvement in wound healing regardless of the cause and location of fibrosis; cells expressing Ang II receptors are primarily myofibroblasts. Therapy with ACE inhibitors and aldosterone receptor antagonist have each been shown to attenuate development of fibrosis.

Aldosterone↗
PubMed1995

Angiotensin-II-induced increase in transcoronary protein clearance: role of hypertension vs. nitric oxide or cyclo-oxygenase products.

Elevations in plasma angiotensin II (AngII) are associated with an efflux of plasma macromolecules into the perivascular and contiguous interstitial space. Whether this exudative response is related to associated hypertension or another effect of AngII is uncertain. We therefore monitored plasma and cardiac lymph total protein, albumin and fibronectin and calculated transvascular clearances for total protein (TVPC) and albumin (TVAC) and lymph fibronectin transport (LFT) every 30 min in open-chested, instrumented dogs. After baseline observations were obtained over 30 min, pressor (250 ng.kg.min-1) or nonpressor (11 ng.kg.min-1) doses of AngII were given intravenously for 90 min. Saline-treated, instrumented dogs served as controls. To address a potential secondary effect of AngII on vascular protein clearance, we monitored lymph prostaglandin E2 and cGMP (a marker of released nitric oxide, NO). At > or = 30 min, each dose of AngII was associated with a significant (P < or = 0.05) and comparable increase in TVPC, TVAC and LFT over baseline, indicating that increase in protein clearance was not related to elevated arterial pressure. Lymph cGMP rose significantly (P < or = 0.05) at 30 min for each dose of AngII and remained elevated thereafter. Lymph PGE2 was increased at > or = 60 min (P < or = 0.05) but only with the pressor dose. To determine the contribution of NO and PGE2 on AngII-induced transcoronary protein clearance, each dose of AngII was accompanied by co-administration of either the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), or the cyclo-oxygenase inhibitor, indomethacin. L-NAME completely inhibited the release of cGMP and the increase in protein clearance was not seen. Indomethacin suppressed the release of PGE2, but did not prevent the increase in protein clearance. Thus, AngII-induced increase in transcoronary protein clearance is not related to arterial hypertension or the release of PGE2, but instead appears to be mediated by NO release.

Angiotensin II↗
PubMed1995

Inhibition of angiotensin-converting enzyme and attenuation of myocardial fibrosis by lisinopril in rats receiving angiotensin II.

High-density angiotensin-converting enzyme (ACE) binding is present in heart valve leaflets and the fibrous tissue that appears in the rat myocardium after either chronic administration of angiotensin II (AngII) or after myocardial infarction. This suggests that connective tissue ACE is independent of circulating AngII and that ACE may be an integral component of normal and pathologic tissue repair. To address this possibility the present study was undertaken. We sought to determine whether the ACE inhibitor lisinopril would attenuate fibrous tissue ACE binding and fibrous tissue formation in the myocardium of rats receiving AngII. Three experimental groups were examined: untreated, age-matched controls; rats receiving subcutaneous AngII (150 ng/min) by minipump for 2 weeks; and rats receiving AngII plus oral lisinopril (20 mg/kg/day) for 2 weeks. Cardiac ACE binding density was localized and quantified by in vitro autoradiography with [125I]-labeled 351A, a tyrosyl derivative of lisinopril, while fibrosis was identified by light microscopy in serial sections stained with picrosirius red. Hematoxylin and eosin and anti-fibronectin antibody were used to identify cardiac myocyte necrosis. Immunohistochemical labeling with alpha-smooth muscle actin was used to identify myofibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1995

Coronary vascular hyperpermeability and angiotensin II.

Elevations in plasma angiotensin II (AngII) are associated with evidence of vascular hyperpermeability expressed as efflux of plasma macromolecules into the perivascular and interstitial space. This exudative response is followed by a series of fibrogenic events that lead to a perivascular fibrosis of involved vessels. Mediators of hyperpermeability and fibrogenesis are unknown. In dogs receiving intravenous AngII, hemodynamic factors (i.e., arterial hypertension or coronary venoconstriction) were discounted as being responsible for the rise in cardiac lymph-to-plasma protein ratio. Accordingly, we investigated the relationship between AngII-induced coronary hyperpermeability and the release of prostaglandin E2 (PGE2) and activation of the basement membrane degrading matrix metalloproteinase, gelatinase/type IV collagenase. In dogs, cardiac lymph was monitored over the course of a 90-minute intravenous infusion of either AngII (0.2 to 0.3 micrograms/kg/min; n = 8) or saline solution (n = 6). Lymph was examined at 30-minute intervals for the following: total protein (Lowry's method), albumin (sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)), plasma fibronectin (SDS-PAGE and enzyme-linked immunosorbent assay); PGE2 (radioimmunoassay) and gelatinase/type IV collagenase (zymography). In comparison with baseline we found a consistent rise in lymph flow (p = 0.02), total protein (p = 0.02), albumin, fibronectin, PGE2 (p = 0.03), and gelatinase/type IV collagenase (p = 0.019), which began after 30 minutes of AngII infusion. Similar trends were not observed in dogs receiving saline solution alone. We therefore conclude that AngII-induced coronary vascular hyperpermeability is associated with an early release of PGE2 and gelatinase.

Angiotensin II↗
PubMed1995

Pharmacological modulation of cardiac fibroblast function.

The cardiac interstitium is composed of nonmyocyte cells and a structural protein network which plays a dominant role in governing the structure, architecture, and mechanical behavior of the myocardium. The heterogeneity in myocardial structure, created by the altered behavior of nonmyocyte cells, particularly cardiac fibroblasts which are responsible for myocardial collagen metabolism and fibrous tissue accumulation, may largely explain the appearance of diastolic and/or systolic myocardial failure. Regulatory mechanisms that are related to the fibrous tissue response in various cardiovascular diseases, e.g., hypertensive heart disease, dilated cardiomyopathy or post myocardial infarction, are of primary clinical interest. A better understanding of the hitherto neglected role of cardiac fibroblasts in mediating an adverse structural remodeling of the myocardium will lead to specific pharmacologic agents that interfere with the fibrous tissue response. Several lines of evidence based on in vivo and in vitro studies suggest that circulating and tissue renin-angiotensin-aldosterone systems (RAAS) are involved in the structural remodeling of the nonmyocyte compartment, including the cardioprotective effects of angiotensin converting enzyme (ACE) inhibition or aldosterone receptor antagonism that was found to prevent myocardial fibrosis in the rat with renovascular or genetic hypertension. In cultured adult cardiac fibroblasts, an angiotensin (Ang)II- or aldosterone-mediated dose-dependent increase in collagen synthesis could be completely abolished by the use of AngII type 1 or mineralocorticoid receptor antagonists, respectively. Likewise, the AngII-mediated decrease in the activity of matrix metalloproteinase 1, the key enzyme for interstitial collagen degradation, could be antagonized by AngII receptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1995

Local regulation of extracellular matrix structure.

The extracellular matrix (ECM) is composed of various collagens, glycosaminoglycans, and elastin bathed by a tissue fluid found throughout the interstitial space. It is this substratum in which fibroblasts and macrophages normally reside, where fibroblast phenotypic transformation occurs, and into which inflammatory cells migrate when called upon during tissue repair. Many diseases, expressed in an organ-specific manner, require organ-specific ECM remodeling. Regulation of fibrillary type I collagen synthesis, whose disproportionate (relative to degradation) accumulation is characteristic of the tissue fibrosis that adversely alters organ function, is therefore of considerable importance. Emerging evidence implicates angiotensin converting enzyme (ACE), found in fibroblast-like cells, and ACE-related peptides, angiotensin II and bradykinin, in serving important regulatory functions that influence wound healing and thereby ECM structure in health and disease. The heart and its collagen matrix have been targeted for discussion in this brief review.

Animals↗