Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While there have been several studies on the actions of opioid peptides on adrenocortical steroidogenesis, the results of these studies have failed to resolve the question as to whether these peptides exert a direct action on the adrenal cortex. The present studies were designed to address this question directly, using collagenase-dispersed rat zona glomerulosa and zonae fasciculata/reticularis cells incubated in vitro. The results obtained clearly show that the opioid peptides tested (beta-endorphin, Leu-enkephalin, Met-enkephalin, and its long-acting analogue, DALA) all exerted a significant stimulatory effect on aldosterone secretion by zona glomerulosa cells and all, except Leu-enkephalin, stimulated corticosterone secretion by inner zone cells. The response was shown to be inhibited by naloxone. There did not appear to be a significant interaction between the effects of ACTH and the opioid peptides on adrenocortical cells. Studies using specific agonists for opioid receptor subtypes (DAMGO, DPDPE and U-50488H, specific for mu, delta and kappa receptors respectively) showed that the effect of opioid peptides on the zona glomerulosa appeared to be mediated exclusively by mu receptors while the response of inner zone cells was mediated by both mu and, to a lesser extent, kappa receptors. Finally, studies on the second messenger systems activated by the opioid peptides and the receptor agonists showed that these peptides act to increase labelling of inositol trisphosphate, and strongly suggest that, in the rat adrenal cortex, both mu and kappa opioid receptors are linked to the activation of phospholipase C.
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PMID:Action of opioid peptides on the rat adrenal cortex: stimulation of steroid secretion through a specific mu opioid receptor. 773 74

Myocardial fibrosis is associated with an activated renin-angiotensin-aldosterone system (RAAS). In renovascular hypertension, this presents as a reactive perivascular and interstitial fibrosis in not only the pressure overloaded, hypertrophied left ventricle but also the normotensive, nonhypertrophied right ventricle. It therefore would appear that circulating hormonal and not hemodynamic factors are responsible for this adverse fibrous tissue response. To ascertain whether the RAAS effector hormones angiotensin II (AII) or aldosterone (ALDO) directly stimulate collagen synthesis or inhibit collagenase production we used cell culture. Adult rat cardiac fibroblasts (Fb) were cultured since these cells express mRNA for types I and III collagens, the major fibrillar collagens in the heart, and collagenase or matrix metalloproteinase 1 (MMP 1), the key enzyme for interstitial collagen degradation. Collagen synthesis, determined by 3H-proline incorporation, and collagenase activity were measured in confluent, quiescent Fb after 24 h incubation with various concentrations of AII or ALDO (10(-11)-10(-6)M) in the presence or absence of either 10(-5)M type 1 (DuP 753) and type 2 (PD 123177) AII or 10(-9)-3 x 10(-6)M ALDO (spironolactone) receptor antagonists, respectively. Collagen synthesis, normalized per total protein synthesis, increased significantly (P < 0.005) after incubation with either 10(-9)M ALDO (5.9 +/- 1.0%) or 10(-7)M AII (5.3 +/- 1.2%) compared with untreated control cells (2.9 +/- 0.5%) of the same passage (p6-p10). This increase in collagen synthesis could be completely abolished by either types 1 or 2 AII receptor antagonists in AII stimulated Fb or the competitive ALDO receptor antagonist, spironolactone, at equimolar concentration in ALDO stimulated Fb. AII significantly decreased collagenase activity which could be completely abolished by PD 123177, but not DuP 753, while ALDO had no effect on collagenase activity. The mineralocorticoid, ALDO, stimulates collagen synthesis in cultured adult rat cardiac Fb in concentrations similar to those found in plasma in renovascular hypertension and this response appears to occur via type I corticoid receptors. AII appears to stimulate collagen synthesis by both type 1 and 2 AII receptors, but only in high concentrations that could be generated locally within the myocardium. In addition, AII unlike ALDO inhibits collagenase activity that could be attenuated only by type 2 receptor blockade. These findings suggest a direct interaction between ALDO, AII and cardiac Fb in mediating myocardial fibrosis in hypertensive heart disease.
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PMID:Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. 796 49

A collagen network, composed largely of type I and III fibrillar collagens, is found in the extracellular space of the myocardium. This network has multiple functions which includes a preservation of tissue architecture and chamber geometry. Given its tensile strength, collagen is a major determinant of tissue stiffness. Its disproportionate accumulation, in the form of either a reactive or a reparative fibrosis, further increases stiffness. A degradation of collagen tethers, on the other hand, is an anatomic requisite for a distortion in tissue architecture and a reduction in stiffness that can lead to chamber dilatation, wall thinning, and even rupture of the myocardium. Collagen turnover in the myocardium is dynamic. When synthesis exceeds degradation, an adverse accumulation of collagen appears to distort tissue structure. This is true for either the hypertrophied and/or nonhypertrophied ventricle. Factors that contribute to the appearance of myocardial fibrosis are largely different from those that promote cardiac myocyte growth. Included amongst these fibrogenic factors are effector hormones of the reinin-angiotensin-aldosterone system (RAAS). Studies conducted both in intact animals (relative to dietary sodium intake) and in cultured adult cardiac fibroblasts have pointed toward the association between collagen accumulation and chronic elevations in circulating angiotensin II and aldosterone. A tissue hormonal system involving angiotensin II, endothelins and bradykinin, may likewise regulate fibrogenesis. In this regard, angiotensin converting enzyme is found in connective tissue of the normal heart, including the matrix of heart valves and the adventitia of the intramural coronary arteries, and fibrous tissue that forms following infarction or with chronic RAAS activation. The importance of ACE in the regulation of local angiotensin II and bradykinin levels and their contribution to collagen turnover is a fruitful area of research with important clinical implications. The myocardium also contains a proteolytic system, including collagenase. The characteristics and regulation of matrix metalloproteinases and their tissue inhibitors in various cardiovascular disease states requires further investigation.
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PMID:Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms. 802 11

The isolated bovine adrenocortical cells are prepared aseptically by the use of collagenase and deoxyribonuclease. The isolated cells are suspended in Ham F-10 medium containing 5% fetal calf serum, 10% newborn calf serum, 2.5% horse serum and antibiotics. The seeded cells are cultured at 37 degrees C in a humidified atmosphere of 5% CO2 in air. Steroidogenic activity for ACTH reached the maximum in the 2- to 3-day primary cultured cells; the maximum response to ACTH in these cells is more intense than that in freshly isolated bovine adrenocortical cells. The primary cultured cells have prostaglandin, muscarinic, ATP and beta-adrenergic receptors that are linked to steroidogenesis in addition to ACTH and aldosterone receptors. Thus primary cultured bovine adrenocortical cells are a useful tool to study these receptors and the intracellular events that are associated with the receptors. We also demonstrated that the fura 2 loaded primary cultured monolayer cells on glass cover slips provide us much more information than suspended cells in the study of intracellular Ca2+ mobilization in adrenocortical cells.
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PMID:[Primary culture of bovine adrenocortical cells]. 811 88

The urinary bladder of Bufo marinus excretes H+ and this excretion is increased by metabolic acidosis (MA), insulin (IN), prostaglandin E2 (PGE2), increases CO2, and aldosterone. The purpose of this experiment was to determine whether MA, IN, PGE2, CO2, and aldosterone stimulate inositol phosphate's (IP) formation in isolated cells of toad urinary bladder. Cells were prepared by treating bladder sacs with collagenase. Cells were obtained from 10 toads in MA and 10 normal toads, suspended in 2 ml of Ringer's solution containing LiCl (10 mM), myo-inositol (5 mM), and [3H]myo-inositol (10 microCi), and then incubated for 2 hr at 25 degrees C. Cells were homogenized and the IP fractions quantitated by column chromatography and liquid scintillation counting. The results were expressed as dpm (mu MPO4)-1 (hr)-1. The IP in MA cells was 44,202 +/- 4,646 and in normal toad cells it was 31,637 +/- 3,613 (P < 0.05). In a separate experiment, cells from 10 paired hemibladders were isolated from normal toads. The cells were treated exactly as above except there were no LiCl in the bath. LiCl was added to all baths after 2 hr and the experimental cells were challenged with IN, PGE2, increases CO2, and aldosterone for 20 min. The IP were quantitated as above. IN treatment stimulated inositol bisphosphate and inositol triphosphate (P < 0.01). PGE2 and increases CO2 also stimulated inositol triphosphate (P < 0.05). Aldosterone did not alter formation of any of the IP fractions. We conclude that MA, IN, PGE2, and increases CO2 stimulate IP formation in cells of toad urinary bladder and inositol triphosphate may be an important second messenger in mediating the response of MA, IN, PGE2, and increases CO2.
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PMID:Stimulation of phosphoinositides by agents that stimulate proton secretion in toad urinary bladder. 841 76

Cardiac fibroblasts appear to be important in producing and maintaining the extracellular matrix (ECM) of the heart. The abnormal proliferation of cardiac fibroblasts and deposition of the ECM protein, collagen, associated with hypertension and myocardial infarction, may adversely affect the performance of the heart. Several groups of factors affect collagen gene expression and/or growth of cardiac fibroblasts. Angiotensin II, aldosterone and endothelins play a central role in the remodeling of the ECM in hypertension, and decrease collagenase activity and/or increase collagen synthesis in cultured cells. Regulatory peptides that are generally elevated at sites of injury, such as TGF-beta 1 and PDGF, increase collagen synthesis and/or stimulate mitogenesis. Mechanical stretch enhances collagen expression and cell proliferation, responses which could in part be due to integrin activation. Cytokines may stimulate or inhibit cell growth, the latter through prostaglandin formation. Angiotensin II is a principal determinant in vivo of cardiac fibroplasia and synthesis of the ECM proteins, collagen and fibronectin. Cardiac fibroblasts possess G-protein-coupled AT1 receptors for angiotensin II that couple to activation of multiple signalling pathways, including: phospholipase C-beta, with the subsequent release of Ca2+ from intracellular stores and activation of protein kinase C, mitogen-activated protein kinases, tyrosine kinases, phospholipase D, phosphatidic acid formation, and the STAT family of transcription factors. Cardiac fibroblasts respond to angiotensin II with hyperplastic/hypertrophic growth, and increased expression of collagen, fibronectin, and integrins. The mechanisms by which the AT1 receptor activates multiple signalling pathways are not known, although the receptor might interact at some level with both integrins and cytokine receptors. Different signalling pathways of the AT1 receptor may subserve different cellular responses, such as mitogenesis, ECM synthesis, or an inflammatory/stress response. Crosstalk among the signalling pathways of the AT1 receptor, and those of G-protein, cytokine, and growth-factor receptors, may determine the ultimate response of the cell.
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PMID:Molecular signalling mechanisms controlling growth and function of cardiac fibroblasts. 857 2

To investigate the hypothesis that aldosterone plays a role in the development of fibrosis, cultured fibroblasts from adult rat heart have been examined for their expression of aldosterone receptors and the effects of aldosterone on collagen synthesis. Binding assays with both 3H-aldosterone and 3H-RU26752 in intact cardiac fibroblasts and cytosolic extracts from cardiac fibroblasts failed to reveal expression of aldosterone receptors. However, using the method of reverse transcription-polymerase chain reaction, we could demonstrate the expression of mRNA for the mineralocorticoid receptor in both cardiac fibroblasts and neonatal rat cardiomyocytes. Functional studies investigating the effect of aldosterone on collagen synthesis (3H-proline incorporation into collagenous protein) revealed that aldosterone does not stimulate collagen synthesis in cardiac fibroblasts at concentrations (10(-8) to 10(-9) M) observed in primary or secondary hyperaldosteronism. At higher concentrations (10(-6) to 10(-7) M) aldosterone inhibited collagen synthesis. Expression of collagen genes I alpha 1, III alpha 1, IV alpha 1 and of the collagenase gene was not affected by aldosterone. The collagen gene VI alpha 2 was also found to be expressed in cultured cardiac fibroblasts, and its expression was also independent of aldosterone. The data indicate that fibrosis is not due to a direct effect of aldosterone on fibroblast collagen synthesis.
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PMID:Does aldosterone-induced cardiac fibrosis involve direct effects on cardiac fibroblasts? 869 56

Joining peptide 1-18 (JP 1-18), added alone in concentrations of 10(-13)-10(-7) M to collagenase-dispersed human adrenocortical cells, did not affect the basal production of corticosterone, cortisol, aldosterone, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS). JP 1-18 potentiated the ACTH-stimulated production of steroids. When administered in combination with histamine (10(-8)-10(-3) M), JP 1-18 (10(-8) or 10(-10) M), enhanced the synthesis of DHEA and DHEAS. JP 1-18, together with histamine, may play a role in the regulation of DHEA and DHEAS production.
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PMID:Effects of joining peptide (1-18) and histamine on dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) production of human adrenocortical cells in vitro. 880 2

Hypoxia in vivo leads to a decrease in aldosterone not completely explained by extrinsic controllers of adrenal function including adrenocorticotrophic hormone, renin-angiotensin II, and K+. The dissociation of renin and aldosterone during acute hypoxia in vivo may be explained by the finding that aldosterone synthesis in adrenal cells is reversibly and specifically inhibited by decreases in O2 levels within the physiological range. The present study investigated whether the direct effect of acute decreases in O2 levels on aldosteronogenic pathway is altered during maturation. Adrenal cells (whole adrenals) were prepared from fetal (27 days gestation), neonatal (1 day), and infant (10 days) New Zealand White rabbits, and capsular cells were prepared from young (21 days) and adult (3 months) rabbits. All cells were dispersed with collagenase. Basal and cAMP-stimulated aldosterone production were assessed under two different levels of O2 (pO2 = 20.0 kPa or pO2 = 8.7 kPa). Decreased O2 levels significantly inhibited cAMP-stimulated aldosterone production in cells obtained from rabbits of all ages by 60 +/- 5% cAMP-stimulated aldosterone production was significantly lower in cells obtained from neonates and premature animals under both normoxic and reduced O2 conditions as compared with animals > or = 10 days old. Corticosterone production by cells obtained from adults and 21-day-old rabbits was unaffected by reduced O2 conditions suggesting a specific effect on the aldosterone pathway. The data demonstrate that the O2 sensitivity of the aldosterone pathway is present throughout development.
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PMID:Aldosterone release from adrenal cells is inhibited by reduced oxygen levels in vitro during maturation in rabbits. 898 36

Hypoxia and fluid and electrolyte disturbances are serious risks to normal postnatal development. Because a decrease in inspired O2 (hypoxic hypoxia) inhibits aldosterone synthesis in the adult and aldosterone controls water and electrolyte balance, we studied adrenocortical function in rabbits exposed to normobaric normoxia or hypoxic hypoxia (fraction of inspired O2 0.09) from birth. At 21 days of age, rabbits were anesthetized, the adrenals were rapidly removed, and the adrenal capsules containing mostly zona glomerulosa cells were separated. Cells were dispersed with collagenase and studied in vitro. Hypoxia in vivo resulted in a 73% decrease in basal aldosterone release and a 86% decrease in adenosine 3',5'-cyclic monophosphate-stimulated aldosterone release in vitro. We hypothesized that increased unesterified fatty acids could be partly responsible for inhibition of aldosterone synthesis. Total serum unesterified fatty acids in hypoxic kits were significantly increased (298 +/- 14 micromol/l) compared with normoxic kits (184 +/- 31 micromol/l). When cells from hypoxic rabbits were washed with fatty acid-free albumin and studied under conditions devoid of fatty acids, aldosterone production was partially restored. Corticosterone production was not affected by washing. Washing had no effect on aldosterone synthesis by cells from normoxic rats. Finally, exposing washed zona glomerulosa cells to oleic acid (10-50 microM) inhibited aldosteronogenesis. We conclude that exposure to hypoxia from birth attenuates aldosterone production in part due to an increase in levels of unesterified fatty acid levels.
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PMID:Effect of exposure to hypoxia from birth on aldosterone in rabbits: role of unesterified fatty acids. 914 5


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