19 results found
Pedersen S, Toe Q, Wort SJ, et al., 2018, Stabilised ferroportin activity affects pulmonary vascular cells responses: implications for pulmonary hypertension, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: European Respiratory Society, ISSN: 0903-1936
Ramakrishnan L, Pedersen SL, Toe QK, et al., 2018, The Hepcidin / Ferroportin axis modulates proliferation of pulmonary artery smooth muscle cells, Scientific Reports, Vol: 8, ISSN: 2045-2322
Studies were undertaken to examine any role for the hepcidin/ferroportin axis in proliferative responses of human pulmonary artery smooth muscle cells (hPASMCs). Entirely novel findings have demonstrated the presence of ferroportin in hPASMCs. Hepcidin treatment caused increased proliferation of these cells most likely by binding ferroportin resulting in internalisation and cellular iron retention. Cellular iron content increased with hepcidin treatment. Stabilisation of ferroportin expression and activity via intervention with the therapeutic monoclonal antibody LY2928057 reversed proliferation and cellular iron accumulation. Additionally, IL-6 treatment was found to enhance proliferation and iron accumulation in hPASMCs; intervention with LY2928057 prevented this response. IL-6 was also found to increase hepcidin transcription and release from hPASMCs suggesting a potential autocrine response. Hepcidin or IL-6 mediated iron accumulation contributes to proliferation in hPASMCs; ferroportin mediated cellular iron excretion limits proliferation. Haemoglobin also caused proliferation of hPASMCs; in other novel findings, CD163, the haemoglobin/haptoglobin receptor, was found on these cells and offers a means for cellular uptake of iron via haemoglobin. Il-6 was also found to modulate CD163 on these cells. These data contribute to a better understanding of how disrupted iron homeostasis may induce vascular remodelling, such as in pulmonary arterial hypertension.
The interplay between iron and oxygen is longstanding and central to all aerobic life. Tight regulation of these interactions including homeostatic regulation of iron utilization ensures safe usage of this limited resource. However, when control is lost adverse events can ensue, which are known to contribute to an array of disease processes. Recently, associations between disrupted iron homeostasis and pulmonary artery hypertension (PAH) have been described with the suggestion that there is a contributory link with disease. This review provides a background for iron regulation in humans, describes PAH classifications, and discusses emerging literature, which suggests a role for disrupted iron homeostatic control in various sub-types of PAH, including a role for decompartmentalization of hemoglobin. Finally, the potential for therapeutic options to restore iron homeostatic balance in PAH are discussed.
Shackshaft T, Wort S, Quinlan G, et al., 2017, Conditioned media from human pulmonary arterial endothelial cells treated with hepcidin or haemoglobin cause proliferation and migration of human pulmonary artery smooth muscle cells, British Thoracic Society Annual Meeting, Publisher: BMJ Publishing Group, Pages: A68-A69, ISSN: 1468-3296
Ramakrishnan L, Anwar A, Wort S, et al., 2016, Haemoglobin mediated proliferation and IL-6 release in human pulmonary artery endothelial cells: a role for CD163 and implications for pulmonary vascular remodelling., Meeting of the British-Thoracic-Society, Publisher: BMJ Publishing Group, Pages: A220-A220, ISSN: 1468-3296
Mumby S, Ramakrishnan L, Kempny A, et al., 2016, Dysregulation of iron homeostasis in Eisenmenger syndrome; comparison to idiopathic pulmonary arterial hypertension and healthy controls., ERS International Congress
Ramakrishnan L, Uhlinger K, Dale L, et al., 2016, ADP-ribosyl cyclases regulate early development of the sea urchin., Messenger, Vol: 5, Pages: 100-106, ISSN: 2167-955X
ADP-ribosyl cyclases are multifunctional enzymes involved in the metabolism of nucleotide derivatives necessary for Ca(2+) signalling such as cADPR and NAADP. Although Ca(2+) signalling is a critical regulator of early development, little is known of the role of ADP-ribosyl cyclases during embryogenesis. Here we analyze the expression, activity and function of ADP-ribosyl cyclases in the embryo of the sea urchin - a key organism for study of both Ca(2+) signalling and embryonic development. ADP-ribosyl cyclase isoforms (SpARC1-4) showed unique changes in expression during early development. These changes were associated with an increase in the ratio of cADPR:NAADP production. Over-expression of SpARC4 (a preferential cyclase) disrupted gastrulation. Our data highlight the importance of ADP-ribosyl cyclases during embryogenesis.
Ramakrishnan L, Mumby S, Wort S, et al., 2015, CD163 is expressed and modulated in human pulmonary artery smooth muscle cells: Implications for Pulmonary Artery Hypertension., ERS Annual Congress
Ramakrishnan L, Mumby S, Wort JS, et al., 2014, Ferroportin is Expressed in Human Pulmonary Artery Smooth Muscle Cells: Implications for Pulmonary Arterial Hypertension., BTS Annual Winter Meeting, Publisher: BMJ Publishing Group, ISSN: 1468-3296
Chowdhury J, Ramakrishnan L, Svermova T, et al., 2014, ROBO1/4-SLIT2 EXPRESSION IN PULMONARY VASCULAR CELLS: IMPLICATIONS FOR PAH?, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A85-A85, ISSN: 0040-6376
Mumby S, Ramakrishnan L, Evans TW, et al., 2014, Methemoglobin-induced signaling and chemokine responses in human alveolar epithelial cells, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 306, Pages: L88-L100, ISSN: 1040-0605
Ramakrishnan L, Mumby S, Meng C, et al., 2013, IL-6 mediated proliferative responses in human pulmonary vascular cells are differentially modulated by Iron/Heme/Hemoglobin, ERS 2013 Annual Congress
Pulmonary Arterial Hypertension (PAH) is characterised by progressive pulmonary vascular remodelling culminating in heart failure. Disrupted iron metabolism and anaemia have been linked to development of PAH suggesting iron supplementation may be beneﬁ cial. However iron compounds are known proliferative agents. IL-6 which is both proinﬂ ammatory and central to iron homeostasis is elevated in PAH. With emerging evidence of minor hemolysis in PAH patients, the availability of heme and/or haemoglobin (Hb) to PVCs may further impact on cellular responses. We aim to address the above issues in this study.Human pulmonary arterial smooth muscle cells (PASMCs) & endothelial cells (PAECs) were exposed to iron (FAC)/Heme/Hb prior to treatment with IL6. Cell proliferation was quantiﬁed by Cyquant. RTPCR for expression of Hepcidin (regulatory hormone), Ferroportin (exporter), HO1, CD163(Hb scavenger) was also performed.IL-6 alone caused proliferation reversed by iron in PASMCs but not in PAECs. Heme restricted while Hb supported proliferation in both cell types. Basal CD163 mRNA was undetectable in PAECs but induced by IL-6. Hepcidin, Ferroportin and HO1 were also contrastingly regulated by IL6.[table1]Thus PVCs respond distinctly to the IL-6 stimulus which is further modulated by the availability of Iron/Heme/Hb. Besides IL-6 differentially regulated mRNA expression of genes involved in iron homeostasis. Further investigation of iron handling in PVCs seems warranted.
Patel M, Svermova T, Ramakrishnan L, et al., 2012, RAGE ACTIVATION AND ENDOTHELIAL CELL INJURY ASSOCIATED WITH CARDIOPULMONARY BYPASS, Winter Meeting of the British-Thoracic-Society 2012, Publisher: BMJ PUBLISHING GROUP, Pages: A36-A37, ISSN: 0040-6376
Churamani D, Geach TJ, Ramakrishnan L, et al., 2012, The Signaling Protein CD38 Is Essential for Early Embryonic Development, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 287, Pages: 6974-6978
Patel S, Ramakrishnan L, Rahman T, et al., 2011, The endo-lysosomal system as an NAADP-sensitive acidic Ca2+ store: Role for the two-pore channels, CELL CALCIUM, Vol: 50, Pages: 157-167, ISSN: 0143-4160
Ramakrishnan L, Muller-Steffner H, Bosc C, et al., 2010, A Single Residue in a Novel ADP-ribosyl Cyclase Controls Production of the Calcium-mobilizing Messengers Cyclic ADP-ribose and Nicotinic Acid Adenine Dinucleotide Phosphate, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 285, Pages: 19900-19909
Churaman D, Boulware MJ, Ramakrishnan L, et al., 2008, Molecular characterization of a novel cell surface ADP-ribosyl cyclase from the sea urchin, CELLULAR SIGNALLING, Vol: 20, Pages: 2347-2355, ISSN: 0898-6568
Mukherjee PK, Latha J, Hadar R, et al., 2004, Role of two G-protein alpha subunits, TgaA and TgaB, in the antagonism of plant pathogens by Trichoderma virens., Appl Environ Microbiol., Vol: 1, Pages: 542-9
Mukherjee PK, Latha J, Hadar R, et al., 2003, TmkA, a mitogen-activated protein kinase of Trichoderma virens, is involved in biocontrol properties and repression of conidiation in the dark., Eukaryot Cell, Vol: 2, Pages: 446-55
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