Search PubMed⌕ Search

Biomedical subjects

Karl T Weber

Publications and source records attributed to Karl T Weber.

At least 37 records · Page 2Linked to original sources
PubMed2005

Animal models of cardiac fibrosis.

A collagen network, composed largely of type I and III fibrillar collagens, is found in the heart's interstitial space. This network has multiple functions, including the preservation of tissue architecture and chamber geometry. Given its tensile strength, type I collagen is a major determinant of tissue stiffness. Its disproportionate accumulation, expressed in morphological terms as tissue fibrosis, increases myocardial passive and active stiffness and contributes to ventricular diastolic and systolic dysfunction. Various animal models of cardiac fibrosis have been used to study its functional consequences and to elucidate factors regulating the cellular and molecular biology of fibrogenesis. Herein, we present our experience and findings with several models of cardiac fibrosis.

Aldosterone↗
PubMed2004

Aldosteronism and a proinflammatory vascular phenotype: role of Mg2+, Ca2+, and H2O2 in peripheral blood mononuclear cells.

BACKGROUND: Chronic, inappropriate (relative to dietary Na+) elevations in circulating aldosterone, such as occur in congestive heart failure, are accompanied by a proinflammatory vascular phenotype involving the coronary and systemic vasculature. An immunostimulatory state with activated peripheral blood mononuclear cells (PBMCs) precedes this phenotype and is induced by a fall in cytosolic free [Mg2+]i and subsequent Ca2+ loading of these cells and transduced by oxidative/nitrosative stress. METHODS AND RESULTS: We sought to further validate this hypothesis in rats with aldosterone/1%NaCl treatment (ALDOST) by using several interventions as cotreatment: a Mg2+-supplemented diet; amlodipine, a CCB; and N-acetylcysteine, an antioxidant. Blood samples were obtained at weeks 1 to 4 of ALDOST to monitor [Mg2+]i, [Ca2+]I, and H2O2 production in PBMCs. Coronal ventricular sections were examined for invading inflammatory cells and 3-nitrotyrosine labeling, a marker of oxidative/nitrosative stress. In response to ALDOST and compared with untreated controls, we found an early and persistent reduction in [Mg2+]i with a subsequent rise in [Ca2+]i and H2O2 production, each of which was either attenuated or abrogated by the Mg2+-supplemented diet and by N-acetylcysteine, whereas amlodipine prevented Ca2+ loading and an altered redox state. Cotreatment with these interventions either markedly attenuated or prevented the appearance of the proinflammatory coronary vascular phenotype and the presence of 3-nitrotyrosine in invading inflammatory cells. CONCLUSIONS: We suggest that the immunostimulatory state that appears during aldosteronism and leads to a proinflammatory coronary vascular phenotype is induced by a fall in [Mg2+]i with Ca2+ loading of PBMCs and is transduced by H2O2 production in these cells.

Acetylcysteine↗
PubMed2004

Efficacy of aldosterone receptor antagonism in heart failure: potential mechanisms.

Results of the Randomized Aldactone Evaluation Study and the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study indicate aldosterone receptor antagonism, together with angiotensin-converting enzyme inhibition and loop diuretics, is a most effective strategy in reducing risk for all-cause and cardiovascular-related mortality and morbidity in patients with symptomatic heart failure. Responsible mechanisms are likely multifactoral. As a circulating hormone, aldosterone has well-known endocrine properties that contribute to the pathophysiology of congestive heart failure. This includes Na+ resorption at the expense of K+ excretion in such tissues as kidneys, colon, sweat, and salivary glands. Mg2+ excretion at these sites is likewise enhanced by aldosterone, whereas adrenal aldosterone secretion is regulated by extracellular Mg2+. Other endocrine actions of aldosterone receptor-ligand binding include: a reduction in biologically active cytosolic-free Mg2+, with intracellular Ca2+ loading in nonepithelial cells such as peripheral blood mononuclear cells; its influence on endothelial cell function; and its central actions, including the choroid plexus, activity of the hypothalamic paraventricular nucleus, and autonomic nervous system. De novo generation of aldosterone within the cardiovasculature is recognized and findings suggest its auto/paracrine properties contribute to tissue repair. Each of these actions is interrupted by aldosterone receptor antagonism and therefore may contribute to its salutary response in heart failure.

Aldosterone↗
PubMed2004

Tissue angiotensin II in the regulation of inflammatory and fibrogenic components of repair in the rat heart.

Quantitative in vitro autoradiography has identified high density ACE and AT(1) receptor binding at sites of cardiac injury in the adult rat, implicating Ang II, generated de novo at these sites (tissue Ang II) in contributing to repair. This hypothesis remains to be tested. In the study reported here we used a time-dependent rat model of cardiac injury wherein plasma levels of renin and Ang II are chronically suppressed by means of continuous treatment with aldosterone (0.75 microg/h) and 1% dietary NaCl. To further address a role for tissue Ang II in tissue repair, we administered oral valsartan (10 mg/kg/day) in combination with aldosterone/NaCl. On days 20 and 30 of each regimen, hearts were examined. In coronal sections, we assessed transcription factor NFkappaB activation (RelA subunit), inflammatory-cell infiltration and appearance of myofibroblasts by immunohistochemistry; mRNA expression of several inflammatory (NFkappaB-related) and fibrogenic (type I collagen) mediators of repair, using quantitative in situ hybridization; and ACE binding density, detected with quantitative in vitro autoradiography. Blood pressure was measured with a tail cuff. Untreated age- and sex-matched rats served as controls. On day 20, we found no evidence of cardiac injury, inflammation, or repair with aldosterone/NaCl treatment, with or without valsartan. In contrast, on day 30 of aldosterone/NaCl treatment, inflammatory cells and alpha-SMA-positive myofibroblasts colocalized with high-density ACE binding and histochemical evidence of fibrillar collagen accumulation at sites of microscopic scarring and perivascular fibrosis of intramyocardial coronary arteries that appeared in both right and left ventricles. The activation of NFkappaB and the increased mRNA expression of ICAM-1, MCP-1, TNF-alpha, TGF-beta(1), PAI-1, and type I collagen were also observed at these sites. Expression of vascular cell adhesion molecule-1 was unchanged. Valsartan significantly reduced (P <.01) the expression of these mediators and attenuated the expression of MCP-1. It reduced microscopic evidence of tissue damage and the extent of fibrosis. Blood pressure was increased in aldosterone-treated rats on days 20 and 30; this increase was suppressed by valsartan. We thus show that in this rat model of long-term aldosterone/NaCl administration, in which circulating Ang II is suppressed, AT(1) receptor-mediated actions of tissue Ang II are involved in regulating the expression of mediators of repair at vascular and nonvascular sites of cardiac injury, thereby implicating autocrine/paracrine properties of tissue Ang II in inflammatory and healing responses.

Aldosterone↗
PubMed2004

Loss of bone minerals and strength in rats with aldosteronism.

Congestive heart failure (CHF) is a clinical syndrome with origins rooted in a salt-avid state largely mediated by effector hormones of the circulating renin-angiotensin-aldosterone system. Other participating neurohormones include catecholamines, endothelin-1, and arginine vasopressin. CHF is accompanied by a systemic illness of uncertain causality. Features include the appearance of oxidative/nitrosative stress and a wasting of tissues including bone. Herein we hypothesized that inappropriate (relative to dietary Na+) elevations in plasma aldosterone (Aldo) contribute to an altered redox state, augmented excretion of divalent cations, and in turn, a loss of bone minerals and strength. In uninephrectomized rats that received chronic Aldo and 1% NaCl treatment for 4-6 wk, we monitored plasma alpha1-antiproteinase activity, which is an inverse correlate of oxidative/nitrosative stress; plasma concentrations of ionized Mg2+ and Ca2+; urinary Mg2+ and Ca2+ excretion; and bone mineral composition and strength to flexure stress. Compared with controls, we found reductions in plasma alpha1-antiproteinase activity and ionized Mg2+ and Ca2+ together with persistently elevated urinary Mg2+ and Ca2+ excretion, a progressive loss of bone mineral density and content with reduced Mg2+ and Ca2+ concentrations, and a reduction in cortical bone strength. Thus the hypermagnesuria and hypercalciuria that accompany chronic Aldo-1% NaCl treatment contribute to the systemic appearance of oxidative/nitrosative stress and a wasting of bone minerals and strength.

Animals↗
PubMed2003

Aldosteronism and peripheral blood mononuclear cell activation: a neuroendocrine-immune interface.

Aldosteronism eventuates in a proinflammatory/fibrogenic vascular phenotype of the heart and systemic organs. It remains uncertain whether peripheral blood mononuclear cells (PBMCs) are activated before tissue invasion by monocytes/macrophages and lymphocytes, as is the case for responsible pathogenic mechanisms. Uninephrectomized rats treated for 4 weeks with dietary 1% NaCl and aldosterone (ALDOST, 0.75 microg/h) with or without spironolactone (Spi, 100 mg/kg per daily gavage) were compared with unoperated/untreated and uninephrectomized/salt-treated controls. Before intramural coronary vascular lesions appeared at week 4 of ALDOST, we found (1) a reduction of PBMC cytosolic free [Mg2+]i, together with intracellular Mg2+ and Ca2+ loading, whereas plasma and cardiac tissue Mg2+ were no different from controls; (2) increased H2O2 production by monocytes and lymphocytes together with upregulated PBMC gene expression of oxidative stress-inducible tyrosine phosphatase and Mn2+-superoxide dismutase and the presence of 3-nitrotyrosine in CD4+ and ED-1-positive inflammatory cells that had invaded intramural coronary arteries; (3) B-cell activation, including transcription of immunoglobulins, intracellular adhesion molecule-1, and CC and CXC chemokines and their receptors; (4) expansion of B lymphocyte subset and myosin heavy chain class II-expressing lymphocytes; and (5) autoreactivity with gene expression for antibodies to acetylcholine receptors and a downregulation of RT-6.2, which is in keeping with cell activation and associated with autoimmunity. Spi cotreatment attenuated the rise in intracellular Ca2+, the appearance of oxidative/nitrosative stress in PBMCs and invading inflammatory cells, and alterations in PBMC transcriptome. Thus, aldosteronism is associated with an activation of circulating immune cells induced by iterations in PBMC divalent cations and transduced by oxidative/nitrosative stress. ALDO receptor antagonism modulates this neuroendocrine-immune interface. The full text of this article is available online at http://www.circresaha.org.

Aldosterone↗
PubMed2003

A neuroendocrine-immune interface. The immunostimulatory state of aldosteronism.

Hypertension is an important determinant of heart failure. Ventricular systolic and/or diastolic dysfunction can eventuate in an activation of the renin-angiotensin-aldosterone system (RAAS). Circulating RAAS effector hormones lead to: the appearance of the congestive heart failure syndrome; and a systemic illness that features oxi/nitrosative stress in various tissues, including blood, together with circulating pro-inflammatory cytokines, anorexia and, ultimately, cachexia. In addition to its well-known endocrine properties, expressed in epithelial cells of classic target tissues, aldosterone (ALDO) has an emerging portfolio of actions in nonclassic target tissues, such as circulating lymphocytes and monocytes (or peripheral blood mononuclear cells [PBMC]). This neuroendocrine-immune interface is based on Na(+)-dependent, ALDO-induced iterations in PBMC cytosolic free [Mg(2+)](i) and [Ca(2+)](i). Ca(2+) loading contributes to an induction of oxi/nitrosative stress and activation of PBMC transcriptome. This immunostimulatory state begets a pro-inflammatory/fibrogenic vascular phenotype involving the heart and systemic organs and can be prevented by either ALDO receptor antagonism or antioxidant. The established efficacy of ALDO receptor antagonism as an integral component of the overall management of symptomatic heart failure may include its immunomodulatory properties. This brief review traces studies that led to and then identified the neuroendocrine-immune interface that accompanies aldosteronism.

Aldosterone↗
PubMed2003

Aldosteronism revisited: perspectives on less well-recognized actions of aldosterone.

Aldosterone is a mineralocorticoid with protean actions in both epithelial and nonepithelial cells. These include endocrine properties of circulating aldosterone that promote Na(+) resorption at the expense of well-recognized K(+) excretion and less well-recognized Mg(2+) excretion in classic target tissues: kidneys, colon, and sweat and salivary glands. The regulation of adrenal aldosterone secretion by [Mg(2+)](o) is also less well appreciated. More recently recognized endocrine actions of aldosterone include induction of Mg(2+) efflux in exchange for Na(+) in such nonepithelial cells as peripheral-blood mononuclear cells and influence on epithelial cells of the choroid plexus, where aldosterone alters the composition of cerebrospinal fluid that contributes to blood-pressure regulation. An association between primary aldosteronism and idiopathic intracranial hypertension has recently been reported. Extraadrenal steroidogenesis with de novo aldosterone production by the cardiovasculature, where its auto-/paracrine properties may contribute to tissue repair at sites of injury, has been observed. These less well-recognized actions of aldosterone have led to a revival of interest in how this steroid molecule contributes to the pathophysiology of various clinical disorders.

Aldosterone↗
PubMed2003

Triplex-forming oligonucleotides as modulators of gene expression.

Triplex-forming oligonucleotides (TFOs) have gained prominence in the recent years because of their potential applications in antigene therapy. In particular they have been used as (i) inducers of site-specific mutations, (ii) reagents that selectively and specifically cleave target DNA, and (iii) as modulators of gene expression. In this mini-review, we have made an attempt to highlight the characteristics of these TFOs and the effects of various modifications in the phosphate backbone as well as in the purine and pyrimidine moieties, which contribute to the stability and efficiency of triplex formation. Studies to explore the mechanism of down-regulation of transcription of various genes suggest that at least some TFOs exert their effect by inhibiting binding of specific transcription factors to their cognate cis-acting elements. Recent reports indicate the presence of these potential triplex-forming DNA structures in the genomes of prokaryotes and eukaryotes that may play a major role in target site selection and chromosome segregation as well as in the cause of heritable diseases. Finally, some potential problems in the development of these TFOs as antigene therapeutic agents have also been discussed.

Animals↗
PubMed2003

RAS and connective tissue in the heart.

Circulating angiotensin (Ang) II has well-known endocrine properties in the cardiovasculature. AngII, produced de novo within the heart, has various autocrine and paracrine properties on resident cells expressed via AT(1) receptor-ligand binding. Herein, we review the heart's renin-angiotensin system and its role in connective tissue turnover involving heart valve leaflets and fibrous tissue that appears at sites of injury, such as following myocardial infarction.

Angiotensin II↗
PubMed2003

Aldosteronism: an immunostimulatory state precedes proinflammatory/fibrogenic cardiac phenotype.

Chronic inappropriate (relative to dietary Na+ intake) elevations in circulating aldosterone (ALDO), termed aldosteronism, are associated with remodeling of intramural arteries of the right and left heart. Lesions appear at week 4 of treatment with ALDO and 1% dietary NaCl in uninephrectomized rats (ALDOST) and include invading monocytes, macrophages and lymphocytes with intracellular evidence of oxidative and nitrosative stress, myofibroblasts, and perivascular fibrosis. In this study, we tested the hypothesis that an immunostimulatory state with activated circulating peripheral blood mononuclear cells (PBMCs) precedes this proinflammatory and profibrogenic cardiac phenotype and is initiated by reduction in the cytosolic free Mg2+ concentration ([Mg2+]i). At 1 and 4 wk of ALDOST (preclinical and clinical stages, respectively), we monitored serum Mg2+, PBMC [Mg2+]i and cytosolic free [Ca2+] (via fluorimetry), and expressed genes (via microchip array) as well as markers of oxidative and nitrosative stress in plasma [alpha1-antiproteinase activity (alpha1-AP)] and cardiac tissue (immunohistochemical detection of gp91phox subunit of NADPH oxidase and 3-nitrotyrosine). Age- and gender-matched unoperated and untreated (UO) rats and uninephrectomized salt-treated (UN) rats served as controls. Serum [Mg2+] was unchanged by ALDOST. In contrast with UO and UN, [Mg2+]i and plasma alpha1-AP were each reduced (P < 0.05) at weeks 1 and 4. The decline in PBMC [Mg2+]i was accompanied by Ca2+ loading. Differential (twofold and higher) expression (up- and downregulation) in PBMC transcriptomes was present at week 1 and progressed at week 4. Involved were genes for the alpha1-isoform of Na+-K+-ATPase, the ATP-dependent Ca2+ pump, antioxidant reserves, inducible nitric oxide synthase, and PBMC activation with autoimmune responses. Expression of 3-nitrotyrosine and activation of gp91phox were seen in inflammatory cells that invaded intramural arteries. Thus early in aldosteronism (preclinical stage), an immunostimulatory state featuring activated circulating PBMCs with reduced ionized [Mg2+]i and oxidative and nitrosative stress precedes and may even predispose to coronary vascular lesions that first appear at week 4.

Animals↗
PubMed2003

Aldosteronism in heart failure: a proinflammatory/fibrogenic cardiac phenotype. Search for biomarkers and potential drug targets.

Heart failure is a major health problem of epidemic proportions. Irrespective of its etiologic origins, a dysfunction of this normally efficient muscular pump is associated with systemic consequences, a progressive downhill clinical course and poor prognosis. Ventricular dysfunction is ultimately accompanied by neurohormonal system activation that accounts for: the congestive heart failure syndrome; an induction of oxi/nitrosative stress; adverse vascular remodeling; and activation of the immune system that contributes to a wasting syndrome known as cardiac cachexia. Circulating effector hormones of the renin-angiotensin-aldosterone system are an integral feature of this neurohormonal activation; they have systemic consequences. Insights into the pathophysiology of heart failure will identify improved methods of prevention, including biomarkers to aid in its detection and identification of risk, and to the development of specific drug targets. Herein we address one aspect of the neurohormonal profile of heart failure, namely that related to aldosteronism. Our focus is directed at the link between aldosteronism and its adverse influence on coronary vasculature structure, a proinflammatory/fibrogenic cardiac phenotype, which is based on an immunostimulatory state that includes activated peripheral blood mononuclear cells.

Aldosterone↗