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Biomedical subjects

Jeanine D'Armiento

Publications and source records attributed to Jeanine D'Armiento.

18 recordsLinked to original sources
PubMed2006

Functional expression of the GABAB receptor in human airway smooth muscle.

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system and exerts its actions via both ionotropic (GABA(A)/GABA(C)) and metabotropic (GABA(B)) receptors (R). In addition to their location on neurons, GABA and functional GABA(B) receptors have been detected in nonneuronal cells in peripheral tissue. Although the GABA(B)R has been shown to function as a prejunctional inhibitory receptor on parasympathetic nerves in the lung, the expression and functional coupling of GABA(B) receptors to G(i) in airway smooth muscle itself have never been described. We detected the mRNA encoding multiple-splice variants of the GABA(B)R1 and GABA(B)R2 in total RNA isolated from native human and guinea pig airway smooth muscle and from RNA isolated from cultured human airway smooth muscle (HASM) cells. Immunoblots identified the GABA(B)R1 and GABA(B)R2 proteins in human native and cultured airway smooth muscle. The GABA(B)R1 protein was immunohistochemically localized to airway smooth muscle in guinea pig tracheal rings. Baclofen, a GABA(B)R agonist, elicited a concentration-dependent stimulation of [(35)S]GTPgammaS binding in HASM homogenates that was abrogated by the GABA(B)R antagonist CGP-35348. Baclofen also inhibited adenylyl cyclase activity and induced ERK phosphorylation in HASM. Another GABA(B)R agonist, SKF-97541, mimicked while pertussis toxin blocked baclofen's effect on ERK phosphorylation, implicating G(i) protein coupling. Functional GABA(B) receptors are expressed in HASM. GABA may modulate an uncharacterized signaling cascade via GABA(B) receptors coupled to the G(i) protein in airway smooth muscle.

Adenylyl Cyclases↗
PubMed2006

Differential expression of WNTs and FRPs in the synovium of rheumatoid arthritis and osteoarthritis.

Synovial cells of the joint play a key role in the progression of rheumatoid arthritis (RA). However, the mechanism(s) that triggers aggression of RA synovial cells but not other arthropathies such as osteoarthritis (OA) is not clear. Here we examined expression of WNT and the WNT inhibitor, secreted frizzled-related protein (FRP), in RA and OA synovium by reverse transcription-PCR. WNT10B was most frequently detected in RA synovium, and FRP1, FRP2, and FRP4 in OA synovium. Immunohistochemistry localized WNT10B and FRP1 in synovial lining cells, fibroblasts, and endothelial cells in RA and OA synovium, respectively, and WNT10B expression was increased in parallel with the degree of inflammatory cell infiltration and tissue fibrosis. Membrane-type 1 matrix metalloproteinse (MT1MMP) was upregulated by WNT10B and activation of WNT signaling. MT1MMP immunolocalized to cells identical to WNT10B and beta-catenin staining. The present study demonstrated that WNTs and FRPs are differentially expressed in RA and OA synovium, and suggests an involvement in the pathology of these diseases.

Arthritis, Rheumatoid↗
PubMed2006

Matrix metalloproteinases in development and disease.

Matrix metalloproteinases (MMPs) are key modulators of many biological processes during pathophysiological events, such as skeletal formation, angiogenesis, cellular migration, inflammation, wound healing, coagulation, lung and cardiovascular diseases, arthritis, and cancer. Twenty-four members of the MMP family have been identified in humans, degrading many components of the extracellular matrix, cellular receptors, and cytokines. This review describes the molecular structure, activation and inhibition, and substrate specificity of MMPs, and their biological function in development and disease.

Animals↗
PubMed2006

Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis.

Cholestasis occurs in a variety of clinical settings and often results in liver injury and secondary biliary fibrosis. Several matrix metalloproteinases (MMPs) are upregulated in the liver during cholestasis. The function of the major interstitial collagenase, MMP-13, in the initial phase of liver fibrosis is unknown. The aim of this study was to evaluate the role of MMP-13 during the development of cholestasis-induced liver fibrosis by comparing wild-type and MMP-13-deficient mice. Cholestasis was induced by bile duct ligation (BDL) for 5 days or 3 weeks. Activation and proliferation of hepatic stellate cells (HSCs) were detected by immunohistochemistry. Expression of MMP-13 mRNA increased significantly in BDL livers of WT mice. After BDL for 3 weeks liver fibrosis was suppressed in MMP-13-deficient mice versus WT animals. Activation and proliferation of HSCs were also suppressed in livers of MMP-13-deficient mice after BDL. To clarify the mechanism of this suppression, samples from 5-day BDL mice were used for evaluation of liver injury. Compared with those in WT animals, serum ALT and the number of hepatic neutrophils were reduced in MMP-13-deficient mice. Increased expression of the mRNA of inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) was significantly suppressed in livers of MMP-13-deficient mice. Upregulation of fibrogenic markers, for example, transforming growth factor beta1 (TGF-beta1), was also significantly suppressed in livers of MMP-13-deficient mice versus in WT mice. In conclusion, distinct from the known function of interstitial collagenase to reduce liver fibrosis by degrading the extracellular matrix, MMP-13 contributes to accelerating fibrogenesis in cholestatic livers by mediating the initial inflammation of the liver.

Animals↗
PubMed2006

Bioactive depsides and anthocyanins from jaboticaba (Myrciaria cauliflora).

A new depside, jaboticabin (1), together with 17 known compounds were isolated from the fruit of jaboticaba (Myrciaria cauliflora). The structure of 1 was elucidated by spectroscopic data interpretation. Known compounds were identified by comparison of their spectroscopic data with literature values or by comparison to authentic standards. Compound 1 and the related depside 2-O-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxyphenylacetic acid (2) significantly inhibited chemokine interleukin (IL)-8 production before and after cigarette smoke treatment of cells. Compound 1 was cytotoxic in the HT29 colon cancer cell line (IC50 = 65 microM), and 2 was active against HCT116 colon cancer cells (IC50 = 30 microM). Compounds 1 and 2 also exhibited antiradical activity in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay (IC50 = 51.4 and 61.8 microM, respectively). Two anthocyanins, cyanidin 3-glucoside (3) and delphinidin 3-glucoside (4), also showed good activity in these assays.

Anthocyanins↗
PubMed2005

Mechanical unloading during left ventricular assist device support increases left ventricular collagen cross-linking and myocardial stiffness.

BACKGROUND: Left ventricular assist devices (LVADs) induce reverse remodeling of the failing heart except for the extracellular matrix, which exhibits additional pathophysiological changes, although their mechanisms and functional consequences are unknown. METHODS AND RESULTS: Hearts were obtained at transplant from patients with idiopathic dilated cardiomyopathy (DCM) not requiring LVAD support (n=30), patients requiring LVAD support (n=16; LVAD duration, 145+/-33 days), and 5 nonfailing hearts. Left (LV) and right ventricular (RV) ex vivo pressure-volume relationships were measured, and chamber and myocardial stiffness constants were determined. Myocardial tissue content of total and cross-linked collagen, collagen types I and III, MMP-1, MMP-9, TIMP-1, and angiotensin (Ang) I and II were measured. LV size, mass, and myocyte diameter decreased after LVAD compared with DCM without LVAD (P<0.05). Total and cross-linked collagen and ratio of type I to III collagen increased in DCM compared with nonfailing hearts and increased further after LVAD (P<0.05 versus DCM and nonfailing). Concomitantly, chamber and myocardial stiffness increased with LVAD. The ratio of MMP-1 to TIMP-1 increased in DCM and almost normalized after LVAD, favoring decreased collagen degradation. Tissue Ang I and II also increased during LVAD. There was no significant change in the RV of LVAD-supported heart compared with DCM. CONCLUSIONS: LVAD support increases LV collagen cross-linking and the ratio of collagen type I to III, which is associated with increased myocardial stiffness. Decreased tissue MMP-1-to-TIMP-1 ratio (decreased degradation) and increased Ang levels (stimulants of synthesis) are likely mechanisms for these changes. Lack of significant effects on the RV suggest that hemodynamic unloading of the LV (not provided to the RV) might be the primary factor that regulates these extracellular matrix changes.

Adult↗
PubMed2004

Extracellular regulated kinase/mitogen activated protein kinase is up-regulated in pulmonary emphysema and mediates matrix metalloproteinase-1 induction by cigarette smoke.

The interstitial collagenase matrix metalloprotein-ase-1 (MMP-1) is up-regulated in the lung during pulmonary emphysema. The mechanisms underlying this aberrant expression are poorly understood. Although cigarette smoking is the predominant cause of emphysema, only 15-20% of smokers develop the disease. To define the signaling pathways activated by smoke and to identify molecules responsible for emphysema-associated MMP-1 expression, we performed several in vitro and in vivo experiments. In this study, we showed that cigarette smoke directly induced MMP-1 mRNA and protein expression and increased the collagenolytic activity of human airway cells. Treatment with various chemical kinase inhibitors revealed that this response was dependent on the extracellular regulated kinase-1/2 (ERK) mitogen activated protein kinase pathway. Cigarette smoke increased phosphorylation of residues Thr-202 and Tyr-204 of ERK in airway lining cells and alveolar macrophages in mice at 10 days and 6 months of exposure. Moreover, analysis of lung tissues from emphysema patients revealed significantly increased ERK activity compared with lungs of control subjects. This ERK activity was evident in airway lining and alveolar cells. The identification of active ERK in the lungs of emphysema patients and the finding that induction of MMP-1 by cigarette smoke in pulmonary epithelial cells is ERK-dependent reveal a molecular mechanism and potential therapeutic target for excessive matrix remodeling in smokers who develop emphysema.

Animals↗
PubMed2003

Increased medial degradation with pseudo-aneurysm formation in apolipoprotein E-knockout mice deficient in tissue inhibitor of metalloproteinases-1.

BACKGROUND: The tissue inhibitor of metalloproteinases-1 (TIMP-1) is expressed in atherosclerotic lesions, where it may play a critical role in regulating the activity of matrix metalloproteinases (MMPs). Several MMPs are overexpressed in the atherosclerotic plaque, and they are believed to contribute to the expansion and rupture of the lesion. METHODS AND RESULTS: The Timp-1-knockout mouse model (Timp-1-/-) was crossed into the apolipoprotein E-knockout (apoE0) background. A study population of male apoE0 mice, half of them deficient in TIMP-1, was fed an atherogenic diet. After 10 weeks of the diet, the mean lesion sizes of the two groups of animals were not significantly different, and the average content of fibrillar collagen and macrophages in the lesions was similar. There was no sign of plaque hemorrhage, even after 22 weeks of high-fat diet, indicating that deficiency in TIMP-1 does not predispose to luminal rupture. However the atherosclerotic lesions of the Timp-1-/0 mice developed more aortic medial ruptures, in which all elastic lamellae of the media were degraded and infiltrated with macrophages, forming pseudo-microaneurysms. After 10 weeks of high-fat diet, the Timp-1-/0/apoE0 mice averaged 1.9+/-1.2 medial ruptures in the proximal aorta, compared with 0.5+/-0.7 for the apoE0 controls (P<0.003). At the site of degradation, in situ zymography revealed that the gelatinolytic activity, mainly associated with macrophages, could be abolished by the addition of MMP inhibitors. CONCLUSIONS: These data strongly suggest that TIMP-1 plays a key role in preventing medial degradation associated with atherosclerosis through its ability to inhibit the MMPs that are involved in the disruption of the media.

Aneurysm, False↗
PubMed2003

Progressive adult-onset emphysema in transgenic mice expressing human MMP-1 in the lung.

Mice with lung-specific expression of human matrix metalloproteinase-1 (MMP-1) develop emphysematous changes similar to those seen in smoking-induced emphysema in humans. Morphometric analyses of three transgenic lines [homozygous colony (Col) 34, Col 50, and Col 64] with varying temporal expression of MMP-1 were undertaken to determine the validity of this animal as a model of adult-onset emphysema. Line 50 mice, which have early expression of MMP-1 (14 days postconception), exhibited morphometric changes by 5 days of age. In contrast, homozygous line 34 and 64 with delayed expression (birth and 2 wk of age) were normal up until 4 wk of age when progressive changes in their mean linear intercept were first noted. In contrast, heterozygous mice from line 34 with lower transgene expression did not develop emphysema until 1 yr of age. The changes in mean linear intercept coincided with an increase in lung compliance. Emphysema in these mice was associated with decreased immunostaining for type III collagen within the alveolar septa. This study provides evidence that MMP-1 induces progressive adult-onset emphysema by the selective degradation of type III collagen within the alveolar wall.

Acute Disease↗
PubMed2003

Decreased elastin in vessel walls puts the pressure on.

Mice haploinsufficient for elastin develop structural changes in vessel walls similar to those seen in patients with mutations in the elastin gene. A new study demonstrates that due to mechanical changes in the vessel wall, these animals exhibit increased mean arterial pressures. The results evoke the possibility that alterations in elastin may contribute to the development of essential hypertension in patients.

Animals↗
PubMed2002

Protein kinase A phosphorylation of the cardiac calcium release channel (ryanodine receptor) in normal and failing hearts. Role of phosphatases and response to isoproterenol.

The cardiac ryanodine receptor/calcium release channel (RyR2) on the sarcoplasmic reticulum (SR) comprises a macromolecular complex that includes a kinase and two phosphatases that are bound to the channel via targeting proteins. We previously found that the RyR2 is protein kinase A (PKA)-hyperphosphorylated in end-stage human heart failure. Because heart failure is a progressive disease that often evolves from hypertrophy, we analyzed the RyR2 macromolecular complex in several animal models of cardiomyopathy that lead to heart failure, including hypertrophy, and at different stages of disease progression. We now show that RyR2 is PKA-hyperphosphorylated in diverse models of heart failure and that the degree of RyR2 PKA phosphorylation correlates with the degree of cardiac dysfunction. Interestingly, we show that RyR2 PKA hyperphosphorylation can be lost during perfusion of isolated hearts due to the activity of the endogenous phosphatases in the RyR2 macromolecular complex. Moreover, infusion of isoproterenol resulted in PKA phosphorylation of RyR2 in rat, indicating that systemic catecholamines can activate phosphorylation of RyR2 in vivo. These studies extend our previous analyses of the RyR2 macromolecular complex, show that both the kinase and phosphatase activities in the macromolecular complex are regulated physiologically in vivo, and suggest that RyR2 PKA hyperphosphorylation is likely a general feature of heart failure.

Animals↗
PubMed2002

Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel.

Sympathetic nervous system (SNS) regulation of cardiac action potential duration (APD) is mediated by beta adrenergic receptor (betaAR) activation, which increases the slow outward potassium ion current (IKS). Mutations in two human I(KS) channel subunits, hKCNQ1 and hKCNE1, prolong APD and cause inherited cardiac arrhythmias known as LQTS (long QT syndrome). We show that betaAR modulation of I(KS) requires targeting of adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (PKA) and protein phosphatase 1 (PP1) to hKCNQ1 through the targeting protein yotiao. Yotiao binds to hKCNQ1 by a leucine zipper motif, which is disrupted by an LQTS mutation (hKCNQ1-G589D). Identification of the hKCNQ1 macromolecular complex provides a mechanism for SNS modulation of cardiac APD through IKS.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2002

Matrix metalloproteinase disruption of the extracellular matrix and cardiac dysfunction.

In the heart, collagens are the major extracellular matrix (ECM) protein. The fibrillar collagens of the heart surround and interconnect myocytes and muscle fibers to provide for muscle fiber and myocyte alignment which imparts mechanical support to the myocardium and governs tissue stiffness. Loss of collagen fibrils and struts are said to lead to myocyte slippage, ventricular dilation, and progressive contractile dysfunction. Failed human hearts examined either at autopsy or explantation invariably exhibit alterations of the ECM primarily due to changes in collagen. Modulation of the balance between matrix synthesis and degradation is important in the process of ventricular remodeling and in the pathophysiology of chronic heart failure. Support for the importance of the ECM and activity of matrix metalloproteinases (MMP) in the development of chronic heart failure has been demonstrated both in animal models of heart disease and in humans. A causative role for the ECM in this process was recently revealed in experiments using a transgenic mouse model that expresses the specific collagen-degrading enzyme, MMP-1, in the heart. These studies demonstrated that chronic expression of MMP-1 leads to dynamic changes in the heart and ultimately results in systolic dysfunction. Multiple studies in animal models have also shown that inhibition of MMP activity in animal models of heart failure have attenuated the onset of left ventricular dilatation. Future studies will determine whether inhibition of MMP activity improves morbidity and mortality in patients with heart failure.

Animals↗
PubMed2002

Tuberous sclerosis-associated lesions of the kidney, brain, and skin are angiogenic neoplasms.

BACKGROUND: Tuberous sclerosis is an autosomal dominant condition characterized by the development of benign neoplasms of the brain, kidney, and skin. Progressive growth and malignant transformation of brain and kidney lesions constitute the major cause of morbidity and mortality in adults with tuberous sclerosis. In addition, growth of skin lesions may be disfiguring to patients. OBJECTIVE: The purpose of this study was to determine whether benign tumors in patients with tuberous sclerosis are angiogenic. METHODS: Brain, kidney, and skin tumors from patients with tuberous sclerosis were stained with CD31, a specific marker of vascular endothelium. In addition, we used Northern blot analysis to demonstrate that renal angiomyolipoma cells express the potent angiogenesis stimulator vascular endothelial growth factor (VEGF). RESULTS: Brain, kidney, and skin neoplasms from patients with tuberous sclerosis are highly angiogenic. Renal angiomyolipoma cells produce the potent angiogenic factor VEGF. CONCLUSION: Benign neoplasms of patients with tuberous sclerosis are highly vascular. Our results provide a rationale for antiangiogenic therapy in the treatment and prevention of tuberous sclerosis-associated neoplasms.

Adult↗
PubMedDate not supplied

Emphysematous changes are caused by degradation of type III collagen in transgenic mice expressing MMP-1.

Disruption of the extracellular matrix is believed to play an important role in the pathogenesis of emphysema. Prior studies have demonstrated that transgenic mice expressing the human tissue collagenase, matrix metalloproteinase 1 (MMP-1), develop emphysema. MMP-1 is a protease with substrate specificity for fibrillar collagen. Type I and III collagens, which are the most abundant proteins within the lungs, are the primary substrates for MMP-1. To assess if type I collagen was indeed the site of action for MMP-1 in these transgenic mice, hybrid mice were generated by crossing the MMP-1 transgenic mice with mice that had degradation-resistant type I collagen. The hybrid mice demonstrated an identical emphysematous phenotype as the MMP-1 transgenic mice, indicating that the degradation of type I collagen was not essential to the development of emphysema in these mice. Immunohistochemical studies in control mice demonstrated that collagen fibers in the alveolar walls and ducts of the normal mouse lungs consist mainly of type III collagen. In the transgenic and hybrid mice, the emphysematous changes, which developed, were associated with a marked decrease in type III collagen in these alveolar structures. These results indicate that MMP-1 generated the emphysematous phenotype via the degradative effect on type III collagen, which is a vital structural element of the alveolar walls. This is the first study to show that a matrix metalloproteinase may cause emphysema via its effects on a specific collagen subtype. As such, it should provide important insight into the mechanisms of this disease in humans.

Animals↗
PubMedDate not supplied

Structural emphysema does not correlate with lung compliance: lessons from the mouse smoking model.

The murine smoke-induced model produces histologic emphysema. The authors sought to assess whether the structural emphysema that occurred correlated with the development of compliance changes. The study exposed 2 strains of mice (CBA/J/J x C57BL/6J and A/J) to chronic cigarette smoke. Lung compliance and morphometry were measured. The smoking model generated significant emphysema in A/J mice in the absence of changes in compliance, lung matrix, or apoptosis. Importantly, there was no correlation between the emphysema measured by lung morphometry and pulmonary compliance. This lack of correlation suggests that the mechanisms involved in anatomic emphysema may be distinct from those that cause the loss of elastic recoil.

Animals↗