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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Connective tissue and repair in the heart. Potential regulatory mechanisms. 775 73

The renin-angiotensin system seems to play an important role in the pathogenesis of renal interstitial fibrosis. However, the potential direct effects of angiotensin II (Ang II) on cultured renal fibroblasts have been little studied. We have observed that rat renal interstitial fibroblasts (NRK 49F cell line) possess AT1 receptors coupled to intracellular calcium mobilization. Exposure of these cells to Ang II induced several short and long growth-related metabolic events mediated by the AT1 receptor, including c-fos gene expression, changes in cell cycle and cell proliferation. Activation of interstitial fibroblasts by Ang II could also contribute to extracellular matrix accumulation. Stimulation with Ang II increased mRNA expression of TGF-beta 1, fibronectin and type I collagen. In fact, Ang II enhanced fibronectin production via AT1 receptors by a process depending on autocrine TGF-beta secretion. The mechanism of some Ang II actions (calcium mobilization and fibronectin production) depended on protein kinase C and tyrosine kinase activation. We further investigated whether renal fibroblasts could express some components of the renin-angiotensin system. These cells constitutively expressed the angiotensinogen gene that was up-regulated by Ang II. Collectively, these results indicate that in renal interstitial fibroblasts Ang II causes hyperplasia and extracellular matrix production via the AT1 receptor. Ang II may initiate a positive feedback regulation of fibroblasts growth, inducing the expression of TGF-beta 1 and angiotensinogen genes. Ang II, acting directly on interstitial fibroblasts, may be implicated in the pathogenesis of renal fibrosis.
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PMID:Angiotensin II modulates cell growth-related events and synthesis of matrix proteins in renal interstitial fibroblasts. 940 95

Tissue repair appears in the infarcted heart at both infarcted and noninfarcted myocardium. Experimental evidence gathered to date indicates that myoFb are the predominant cell responsible for collagen formation at sites of repair in the rat heart and related structures. These phenotypically transformed fibroblast-like cells are not normal residents of ventricular tissue. They appear on day 4 at sites of injury and remain abundant for weeks therefore. MyoFb express type I collagen mRNA and ACE and AT1 receptors. ACE inhibitors or AT1 receptor antagonists attenuate collagen accumulation in both infarcted and noninfarcted myocardium. These findings suggest locally generated AngII may have an autocrine function in regulating myoFb collagen turnover.
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PMID:Local angiotensin II and myocardial fibrosis. 943 11

Myofibroblasts and their potential to generate angiotensin (Ang) II and transforming growth factor beta 1 (TGF-beta 1) at sites of infarction in the rat heart have been implicated in tissue repair. These cells likewise contribute to repair in a subcutaneous pouch model of fibrous tissue formation. Their appearance in pouch tissue coincides with high density ACE and Ang II receptor binding, suggesting a role for Ang II in tissue repair. Using pouch tissue studied at different time points of repair, the present study examined the expression of requisite mRNA for Ang peptide generation: angiotensinogen, Ao; an aspartyl protease, either cathepsin-D, Cat-D, or renin: and angiotensin converting enzyme, ACE, TGF-beta 1 and type I collagen mRNA expression was also addressed. Unlike pouch studied on day 2 and 4, at 7, 14 and 21 days, we found: (a) expression of Ao, Cat-D but not renin, ACE and TGF-beta 1 mRNA; (b) Ang I and Ang II peptides in pouch tissue and exudate; (c) the presence of Cat-D activity but no renin activity; (d) an increase in type I collagen mRNA with time; (e) upregulation of pouch tissue ACE mRNA expression by lisinopril treatment, whereas AT1 and AT2 receptor antagonists (losartan and PD 123177, respectively) downregulated the expression of mRNA for ACE, when compared to untreated controls; (f) downregulation of TGF-beta 1 mRNA expression by lisinopril and losartan compared to untreated controls; and (g) PD 123177 had no effect, whereas lisinopril and losartan treatment significantly (P < 0.05) reduced type I collagen mRNA expression. Thus, in this model of fibrous tissue formation, we found expression of component genes involved in Ang peptide (I and II) and TGF-beta 1 generation and Ang II upregulation of TGF-beta 1 expression, suggesting Ang II and/or TGF-beta 1 may upregulate type I collagen expression during tissue repair. Pharmacologic intervention studies with lisinopril or losartan indicate Ang II plays a role in the reciprocal regulation of ACE mRNA expression, which modulates Ang II levels at sites of repair.
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PMID:Pouch tissue and angiotensin peptide generation. 971 Aug 8

Tissue repair following myocardial infarction (MI) eventuates in fibrous tissue formation at the site of myocyte necrosis. Following a large transmural MI, fibrosis appears remote to the infarct site. This is associated with extensive tissue remodeling that adversely affects ventricular diastolic function. Substances involved in promoting fibrous tissue formation at MI and remote sites are under investigation. Angiotensin II (AngII), generated at sites of repair, has been implicated. However, its regulatory role on fibrous tissue formation remains uncertain. In the present study we sought to determine whether AngII is correlated to transforming growth factor beta 1 (TGF-beta1) expression, a regulator of fibrous tissue formation, at these sites of tissue repair. We studied: (1) localization and expression of angiotensin converting enzyme (ACE), AngII receptors, TGF-beta1 mRNA and its receptors in the infarcted rat heart; and (2) effect of AngII on TGF-beta1 synthesis by chronic blockade of AT1 receptors began at the time of surgery by losartan in rats with MI. Hearts were studied at 4 weeks post-MI. We found: (1) low-density ACE, AngII and TGF-beta1 receptor binding and low mRNA for type I collagen and TGF-beta1 in the normal heart; (2) fibrosis at sites of MI and remote to it, including endocardium and fibrosis of intraventricular septum, interstitial fibrosis of non-infarcted myocardium and fibrosis of visceral pericardium; (3) markedly increased (P<0.01) and colocalized ACE, AngII and TGF-beta1 receptor binding, type I collagen and TGF-beta1 mRNA at MI and remote sites of repair; (4) increased TGF-beta1 concentration (P<0. 01) at these sites; and (5) attenuated TGF-beta1 and type I collagen gene expression (P<0.01) at these sites in rats receiving losartan. These observations suggest locally generated AngII via ATi receptor binding is correlated to TGF-beta1 expression and synthesis at sites of repair and remote sites in the infarcted rat heart. The mechanism responsible for the role of AngII in TGF-beta1 remains to be elucidated.
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PMID:Angiotensin II, transforming growth factor-beta1 and repair in the infarcted heart. 973 42

Mesangial cells are one of the main targets of angiotensin II (AngII) in the renal cortex. AngII receptors on mesangial cells are of high affinity (nanomolar range). They belong to the AT1 subtype as shown by the inhibitory effect of AT1 antagonists on [125I]-Sar1, Ala8 AngII binding and on all of the biologic effects mediated by AngII, such as cytosolic calcium stimulation, inositol phosphate formation, prostaglandin production, and cell contraction. AngII also exerts long-term effects on mesangial cells, including stimulation of cell growth and synthesis of a variety of proteins, essentially the components of the extracellular matrix (collagen, fibronectin) and the type 1 inhibitor of plasminogen activator. These effects are mediated, at least in part, by autocrine products, in particular endothelin, platelet-derived growth factor, and transforming growth factor-beta, whose synthesis is enhanced by AngII. Treatment by an AT1 receptor blocker of mice with experimental nephritis inhibits activation of type I collagen alpha2 chain promoter and prevents the development of glomerulosclerosis. AngII receptors in rat mesangial cells are equally distributed between the AT1A and AT1B isoforms. Treatment of these cells by AngII or losartan, an AT1 receptor blocker, has no effect on AT1A and AT1B receptor mRNA expression, whereas candesartan, another AT1 receptor blocker, increases and dexamethasone decreases this expression.
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PMID:Mesangial AT1 receptors: expression, signaling, and regulation. 989 39

Infarct scar, a requisite to the rebuilding of necrotic myocardium following myocardial infarction (MI), has long been considered inert. Earlier morphologic studies suggested healing at the infarct site was complete within 6-8 weeks following MI and resultant scar tissue, albeit necessary, was acellular and simply fibrillar collagen. Utilizing molecular and cellular biologic technologies, recent studies indicate otherwise. Infarct scar is composed of phenotypically transformed fibroblast-like cells, termed myofibroblasts (myoFb) because they express alpha-smooth muscle actin (alpha-SMA) and these microfilaments confer contractile behavior in response to various peptides and amines. These cells are nourished by a neovasculature and are persistent at the MI site, where they are metabolically active expressing components requisite to angiotensin (Ang) peptide generation, including converting enzyme, receptors for AngII and transforming growth factor (TGF)-beta1. They continue to elaborate fibrillar type I collagen. Their generation of these peptides contribute to ongoing scar tissue collagen turnover and to fibrous tissue formation of noninfarcted myocardium. Infarct scar contraction accounts for its thinning and its tonus may contribute to abnormal ventricular chamber stiffness with diastolic dysfunction. Infarct scar is a dynamic tissue: cellular, vascularized, metabolically active and contractile. Pharmacologic interventions with angiotensin converting enzyme inhibitor or AT1 receptor antagonist has proven effective in attenuating scar tissue metabolic activity and minimizing adverse accumulation of fibrous tissue in noninfarcted myocardium.
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PMID:Infarct scar: a dynamic tissue. 1077 28

The alveolar epithelium consists of two cell types, alveolar type I (AT1) and alveolar type II (AT2) cells. We have recently shown that 7-day-old cultures of AT2 cells grown on a type I collagen/fibronectin matrix develop phenotypic characteristics of AT1 cells, display a distinct connexin profile, and coordinate mechanically induced intercellular Ca(2+) changes via gap junctions (25). In this study, we cultured AT2 cells for 7 days on matrix supplemented with laminin-5 and/or in the presence of keratinocyte growth factor. Under these conditions, cultured AT2 cells display AT2 type morphology, express the AT2-specific marker surfactant protein C, and do not express AT1-specific cell marker aquaporin 5, all consistent with maintenance of AT2 phenotype. These AT2-like cells also coordinate mechanically induced intercellular Ca(2+) signaling, but, unlike AT1-like cells, do so by using extracellular nucleotide triphosphate release. Additionally, cultured cells that retain AT2 cell-specific markers express connexin profiles different from cultured cells with AT1 characteristics. The parallel changes in intercellular Ca(2+) signaling with cell differentiation suggest that cell signaling mechanisms are an intrinsic component of lung alveolar cell phenotype. Because lung epithelial injury is accompanied by extracellular matrix and growth factor changes, followed by extensive cell division, differentiation, and migration of AT2 progenitor cells, we suggest that similar changes may be vital to the lung recovery and repair process in vivo.
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PMID:Modulation of pulmonary alveolar type II cell phenotype and communication by extracellular matrix and KGF. 1154 67

The regulation of angiogenesis involves complex interactions. The aim of our study was to assess the influence of angiotensin II (ANG II) on different vascular beds in rat. Aortic, renal and mesenteric rings from 10 male Sprague-Dawley rats were cultured using a three-dimensional culture system consisting of rat type I collagen lattice. We assessed the influence of different ANG II concentrations (10(-7) et 10(-9) mol/L) on these rings as well as the effect of AT1 blockade by losartan (10(-7 mol/L). ANG II inhibited angiogenesis at 10(-7) mol/L on renal artery. However, these was a angiogenic effect at 10(-9) mol/L on the mesenteric artery. Every time losartan prevented the effect of ANG II in any kind of vessel rings. No significant effect on ANG II was found on aortic rings but coadministration of losartan induced a dramatic decrease in the number of capillary sprouts. In conclusion, ANG II seems to be deeply involved in angiogenesis. However, its effect depends on the concentration of ANG II and the type of vessel. ANG II appears to be angiogenic on mesenteric arteries via an AT1 receptor effect and mostly anti-angiogenic on the renal arteries with possible involvement of AT2 receptors.
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PMID:[Influence of angiotensin I on angiogenesis in vitro in the rat]. 1294 28

Angiotensin II is critically involved in skin wound healing, but the underlying mechanism remains unclear. This study investigated the effect of angiotensin II on type I collagen gene activation in human dermal fibroblasts and the possible mechanism involved. Angiotensin II stimulated the mRNA and protein expression of type I collagen and TGF-beta1. Effects were abolished by the angiotensin AT1 receptor antagonist ZD7155 but not by the AT2 blocker PD123319. Blockade of TGF-beta1 markedly inhibited angiotensin II-induced type I collagen gene expression. Activator protein-1 (AP-1) decoy ODNs transfection suppressed angiotensin II-induced TGF-beta1 expression, and also, diminished type I collagen expression. These data indicated that angiotensin II induces collagen gene activation in human dermal fibroblasts through an AT1-mediated AP-1/TGF-beta1 signaling pathway.
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PMID:Angiotensin II induces type I collagen gene expression in human dermal fibroblasts through an AP-1/TGF-beta1-dependent pathway. 1946 3


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