Browsing by Author "Shivakumar, K"

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    Alterations in collagen metabolism and increased fibroproliferation in the heart in cerium-treated rats - Implications for the pathogenesis of endomyocardial fibrosis
    (BIOLOGICAL TRACE ELEMENT RESEARCH, 1998) Kumar, BP; Shivakumar, K
    Cerium (Ce), a rare earth element, has been postulated to play a role in the pathogenesis of tropical endomyocardial fibrosis (EMF). Investigations carried out recently in pursuance of the postulation furnished histological evidence of EMF and increased cardiac collagen content in rats on prolonged administration of Ce. The present study was undertaken to understand the molecular basis of myocardial injury and fibrosis produced by the element. This article presents evidence of increased lipid peroxidation and elevated rates of fibroblast proliferation and collagen deposition in the heart in Ce-treated rats. It is suggested that the element may trigger a wound-healing response in the cardiac tissue leading to cardiac fibrosis.
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    Alterations in collagen metabolism and increased fibroproliferation in the heart in cerium-treated rats: implications for the pathogenesis of endomyocardial fibrosis.
    (Biological trace element research, 1998)
    Cerium (Ce), a rare earth element, has been postulated to play a role in the pathogenesis of tropical endomyocardial fibrosis (EMF). Investigations carried out recently in pursuance of the postulation furnished histological evidence of EMF and increased cardiac collagen content in rats on prolonged administration of Ce. The present study was undertaken to understand the molecular basis of myocardial injury and fibrosis produced by the element. This article presents evidence of increased lipid peroxidation and elevated rates of fibroblast proliferation and collagen deposition in the heart in Ce-treated rats. It is suggested that the element may trigger a wound-healing response in the cardiac tissue leading to cardiac fibrosis.
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    Calcium- and superoxide anion-mediated mitogenic action of substance P on cardiac fibroblasts
    (AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2002)
    Substance P is released from nerve endings in the heart under pathological conditions like ischemia, but its action on cardiac cells has not been investigated. This study tested the hypothesis that substance P is mitogenic to adult cardiac fibroblasts and delineated the underlying mechanism(s). Substance P, acting via neurokinin-1 (NK-1) receptors, stimulated cellular hyperplasia over a range of 1-10 mumol/l. It elicited no change in net collagen production, total protein synthesis, or cell protein content but increased Ca-45 uptake and superoxide generation. EGTA, N-acetyl-cysteine, and superoxide dismutase attenuated the hyperplastic response to substance P. A combination of substance P and EGTA enhanced superoxide generation without an increase in DNA synthesis, showing that an increase in superoxide production does not result in hyperplasia when extracellular Ca2+ is chelated. Together, the data suggest that substance P may activate, via NK-1 receptors, a hyperplastic but not hypertrophic response in adult cardiac fibroblasts and that alterations in redox state and Ca2+ homeostasis may act in concert to mediate its mitogenic action.
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    Cardiac fibrogenesis in magnesium deficiency: a role for circulating angiotensin II and aldosterone
    (AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2006)
    Mechanisms underlying cardiac fibrogenesis in magnesium deficiency are unclear. It was reported earlier from this laboratory that serum from magnesium-deficient rats has a more pronounced stimulatory effect on cell proliferation, net collagen production, and superoxide generation in adult rat cardiac fibroblasts than serum from rats on the control diet. The profibrotic serum factors were, however, not identified. This study tested the hypothesis that circulating angiotensin II may modulate cardiac fibroblast activity in hypomagnesemic rats. Male Sprague-Dawley rats were pair-fed a magnesium-deficient ( 0.0008% Mg) or -sufficient ( 0.05%) diet for 6 days, and the effects of serum from these rats on [ H-3] thymidine and [ H-3] proline incorporation into cardiac fibroblasts from young adult rats were evaluated in the presence of losartan, an angiotensin II type 1 ( AT(1)) receptor antagonist, and spironolactone, an aldosterone antagonist. Losartan and spironolactone markedly attenuated the stimulatory effects in vitro of serum from the magnesium-deficient and control groups, but the inhibitory effects were considerably higher in cells exposed to serum from magnesium-deficient animals. Circulating and cardiac tissue levels of angiotensin II were significantly elevated in magnesium-deficient animals ( 67.6% and 93.1%, respectively, vs. control). Plasma renin activity was 61.9% higher in magnesium-deficient rats, but serum angiotensin-converting enzyme activity was comparable in the two groups. Furthermore, preliminary experiments in vivo using enalapril supported a role for angiotensin II in magnesium deficiency. There was no significant difference between the groups in serum aldosterone levels. The findings suggest that circulating angiotensin II and aldosterone may stimulate fibroblast activity and contribute to a fibrogenic response in the heart in magnesium deficiency.
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    Cerium stimulates protein biosynthesis in rat heart in vivo
    (BIOLOGICAL TRACE ELEMENT RESEARCH, 1995)
    The aim of the study was to ascertain whether Ce, a lanthanide that has been implicated in the pathogenesis of tropical endomyocardial fibrosis, interferes with the biosynthetic repertoire of the cardiac muscle in vivo. Female Sprague-Dawley rats received Ce chloride iv at 1.3 mg/kg body wt.; controls received an equal volume of physiological saline. Rates of protein synthesis and transcription in cardiac muscle, measured in terms of incorporation of (H-3)-phenylalanine and (H-3)-uridine, respectively, into trichloroacetic acid-insoluble material were found to be significantly higher in Ce-treated animals. As low levels of Ce were earlier shown to stimulate collagen as well as noncollagen protein synthesis in cardiac fibroblasts in vitro, the stimulatory effect of the element in vivo reported here supports the speculation that it may influence the expression of proteins Like collagen in the heart and contribute to their accumulation as in endomyocardial fibrosis.
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    cIAP-2 protects cardiac fibroblasts from oxidative damage: An obligate regulatory role for ERK1/2 MAPK and NF-kappa B
    (JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2013) Philip, L; Shivakumar, K
    Cardiac fibroblasts are resistant to several pro-apoptotic factors that prevail in the diseased myocardium. Resistance to death signals may, in the short-term, enable these cells to play a central role in tissue repair following myocyte loss but, in the long-term, facilitate their persistence in the infarct scar, resulting in disproportionate stromal growth and pump dysfunction. Surprisingly, the molecular basis of apoptosis resistance in cardiac fibroblasts remains unclear. We explored the recruitment of anti-apoptotic mechanisms in cardiac fibroblasts subjected to oxidative stress, a major component of ischemia-reperfusion injury and heart failure. Cardiac fibroblasts exposed to H2O2 expressed enhanced levels of anti-apoptotic cIAP-2 mRNA and protein, revealed by real time PCR and western blot analysis, respectively. Pulmonary fibroblasts did not express cIAP-2 and were more susceptible than cardiac fibroblasts to H2O2. cIAP-2 knockdown by RNA interference promoted apoptosis in H2O2-treated cardiac fibroblasts. Electrophoretic mobility shift assay showed NF-kappa B activation in cells under oxidative stress. NF-kappa B inhibition in H2O2-treated cells resulted in significant attenuation of cIAP-2 mRNA and protein expression and apoptosis, indicating involvement of NF-kappa B in cell survival via regulation of cIAP-2. Further, pCMV promoter-driven constitutive expression of cIAP-2 reduced viability loss in NF-kappa B-inhibited cardiac fibroblasts exposed to oxidative stress. H2O2 also caused ERK1/2 activation, which, upon inhibition, prevented I kappa B alpha degradation and nuclear translocation of NF-kappa B. Moreover, ERK1/2 inhibition attenuated H2O2-induced cIAP-2 expression and compromised viability in H2O2-treated cardiac fibroblasts. We propose for the first time that ERK1/2-dependent activation of NF-kappa B and consequent induction of cIAP-2 protects cardiac fibroblasts from oxidative damage. (C) 2013 Elsevier Ltd. All rights reserved.
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    Depressed antioxidant defense in rat heart in experimental magnesium deficiency - Implications for the pathogenesis of myocardial lesions
    (BIOLOGICAL TRACE ELEMENT RESEARCH, 1997)
    Magnesium (Mg) deficiency has been shown to produce myocardial lesions in different experimental models. Based on several lines of evidence, it has been proposed that oxidative injury to the cardiac muscle may explain the pathobiology of such lesions. In pursuance of this postulation, the present study examined the effect of dietary deficiency of Mg on the activity of the antioxidant enzymes, superoxide dismutase (SOD) and catalase, in rat heart. This article reports a significant lowering of the activity of both these enzymes in the cardiac tissue in Mg-deficient rats. Since depressed antioxidant defense in the heart may enhance myocardial susceptibility to oxidative injury, the observation is of possible relevance to the pathogenesis of cardiac lesions in Mg deficiency.
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    Differential response of cardiac fibroblasts from young adult and senescent rats to ANG II
    (AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2003)
    The intracardiac ANG II-forming pathway is activated in the senescent myocardium, raising the possibility of enhanced ANG II effects on cardiac fibroblasts. This study established an in vitro model of cultured cardiac fibroblasts from aged rats to examine if the response of these cells to ANG II is modified in the aged heart. Levels of mRNA encoding renin, angiotensinogen, and the AT(1) receptor subtype in cardiac fibroblasts from young adult and senescent rats were quantified by RT-PCR, net collagen production by a hydroxyproline-based assay, and transforming growth factor (TGF)-beta levels using a commercial kit. In cardiac fibroblasts from young adult rats, ANG II significantly enhanced AT(1) mRNA levels, net collagen production, and TGF-beta production. In fibroblasts from the aged myocardium, ANG II downregulated AT(1) mRNA expression, had a less pronounced effect on net collagen production, and had no effect on TGF-beta production. Such age-related modification of the response of cardiac fibroblasts to ANG II may counteract the effects of augmented intracardiac ANG II production in the senescent heart, limiting fibrogenesis.
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    L-type calcium channel blockers and EGTA enhance superoxide production in cardiac fibroblasts
    (JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2001)
    Since the recognition of the importance of calcium ions to cardiac contractility, the effects of alterations in calcium homeostasis on cardiac myocyte function have attracted immense attention. However, the possibility that changes in extracellular calcium concentration or the administration of calcium channel blockers may exert significant effects on cardiac fibroblasts has not hitherto been explored. This communication presents evidence, for the first time, that EGTA, calcium-free incubation and L-type calcium channel blockers increase endogenous superoxide production in adult rat cardiac fibroblasts. A combination of ryanodine and EGTA was found to have an even greater effect. The observations indicate that extracellular calcium levels influence endogenous superoxide production in cardiac fibroblasts and support the postulation that myocardial fibroblasts may contribute to the cardiac effects of calcium channel blockers and alterations in extracellular calcium concentration. (C) 2001 Academic Press.
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    Magnesium deficiency and cerium promote fibrogenesis in rat heart
    (BULLETIN OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY, 1996)
    Cerium is a biologically active lanthanide and a major constituent of monazite. The observation that inhalation of particles of cerium causes pneumoconiosis had generated considerable interest in the toxicology of the element (Venugopal and Luckey 1978; Vocatura et al 1983). Cerium tartrate was found to produce cardiac injury and polycythaemia in small animals (Venugopal and Luckey 1978). More recently, tropical endomyocardial fibrosis (EMF), a restrictive cardiomyopathy, was postulated to be the cardiac expression of cerium toxicity in combination with magnesium deficiency (Valiathan et al 1989; Valiathan and Kartha 1990). The postulation was based upon the observation of elevated levels of cerium and depressed levels of magnesium in the cardiac tissue of patients with EMF (Valiathan et al 1989; Valiathan and Kartha 1990). Studies carried out in pursuance of the hypothesis showed that tissue levels of cerium are enhanced in magnesium deficiency (Eapen et al 1996) and that cerium and magnesium deficiency have a synergistic effect on cardiac metabolism (Gunther 1990; Shivakumar and Renuka Nair 1991). Importantly, recent observations on the mode of action of cerium at the molecular level suggested that the element may influence expression of matrix proteins like collagen in the heart and produce fibrosis (Prakash et al 1995; Shivakumar et al 1992). A sequel to these earlier investigations, the present study examined whether chronic ingestion of low doses of cerium would produce cardiac fibrosis in experimental animals. This communication presents evidence that cerium per se or in combination with magnesium deficiency produces subendocardial fibrosis and increase in interstitial cellularity and collagen content in rat heart. It also confirms the earlier observation from this laboratory that magnesium deficiency promotes accumulation of cerium in the cardiac tissue (Eapen el al 1996).
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    Magnesium deficiency enhances oxidative stress and collagen synthesis in vivo in the aorta of rats
    (INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 1997)
    Magnesium deficiency has been shown to produce vascular lesions in experimental animals, but the underlying mechanisms of vascular injury are not clear. It has been reported that in rodents, magnesium deficiency enhances circulating levels of factors that promote free radical generation and are mitogenic, In pursuance of these observations, the present study tested the hypothesis that magnesium deficiency may enhance oxidative stress and trigger an accelerated growth response in vivo in the aorta of rats. Oxidative stress mas evaluated in terms of levels of thiobarbituric acid-reactive substances in the serum and aorta and activity of superoxide dismutase and catalase in the aorta; fractional rates of collagen synthesis were assessed using [H-3]-proline. Serum and tissue levels of magnesium and calcium were determined by atomic absorption spectrophotometry, The present study demonstrated for the first time that magnesium deficiency significantly (P < 0.001) increases levels of thiobarbituric acid-reactive substances in the aorta of rats, Other changes in the aorta of animals on the Mg-deficient diet included a significant reduction (54%, P < 0.001) in the activity of superoxide dismutase and catalase (37%, P < 0.01) and a 19% increase in net fractional rates of collagen synthesis (P < 0.05), While serum magnesium was significantly reduced in these animals (P < 0.001), aortic tissue levels of magnesium in these animals remained unaltered throughout the duration of the study, suggesting the existence of other control mechanisms, apart from reduced tissue levels of magnesium, mediating the observed effects. These findings suggest that magnesium deficiency may trigger a wound healing response, involving oxidative injury and growth stimulation, in the vascular system. (C) 1997 Elsevier Science Ltd. All rights reserved.
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    Magnesium deficiency-related changes in lipid peroxidation and collagen metabolism in vivo in rat heart
    (INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 1997)
    Magnesium deficiency is known to produce a cardiomyopathy, characterised by myocardial necrosis and fibrosis. As part of the ongoing investigations in this laboratory to establish the biochemical correlates of these histological changes, the present study probed the extent of lipid peroxidation and alterations in collagen metabolism in the heart in rats fed a magnesium-deficient diet for 28, 60 or 80 days. While lipid peroxidation was measured by the thiobarbituric acid reaction, collagen turnover rates and fibroblast proliferation were assessed using [H-3]-proline and [H-3]-thymidine, respectively. Tissue levels of magnesium and calcium were determined by atomic absorption spectrophotometry. A 39% increase in the cardiac tissue level of thiobarbituric acid reactive substances was observed on day 60 of deficiency (p < 0.001). A marked drop in collagen deposition rate (59%, p < 0.001%) on day 28 but a significant rise in fractional synthesis rate (12%, p < 0.001) and collagen deposition rate (24%, p < 0.001) on day 60 were observed. A fibroproliferative response in the heart was evident on day 80 but not at earlier time-points. Thus, the present study provides evidence of increased lipid peroxidation and net deposition of collagen in the myocardium in response to dietary deficiency of magnesium. These changes were, however, not directly related to alterations in the tissue levels of Mg. It is suggested that the increase in cardiac collagen synthesis and fibroplasia associated with Mg deficiency may represent reparative fibrogenesis, upon oxidative damage to the cardiac muscle, and is mediated by a mechanism independent of changes in cardiac tissue levels of Mg. (C) 1997 Elsevier Science Ltd.
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    Mechanisms in cardiac fibroblast growth: an obligate role for Skp2 and FOXO3a in ERK1/2 MAPK-dependent regulation of p27(kip1)
    (AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2014) Pramod, S; Shivakumar, K
    Cardiac fibroblast hyperplasia associated with enhanced matrix deposition is a major determinant of tissue remodeling in several disease states of the heart. However, mechanisms controlling cell cycle progression in cardiac fibroblasts remain unexplored. Identification of cell cycle regulatory elements in these cells is important to develop strategies to check adverse cardiac remodeling under pathological conditions. This study sought to probe the mechanisms underlying ERK1/2-mediated p27(Kip1) regulation in mitogenically stimulated cardiac fibroblasts. Addition of 10% fetal calf serum to quiescent cultures of adult rat cardiac fibroblasts promoted ERK1/2 activation, as evidenced by its phosphorylation status. Reduction in [H-3]thymidine incorporation into DNA increased population doubling time, flow cytometry, and Western blot analysis showing reduced levels of cyclins D and A, p27(Kip1) induction, and retinoblastoma protein (Rb) hypophosphorylation in ERK1/2-inhibited cells indicated ERK1/2 dependence of G(1)-S transition in cardiac fibroblasts. Lack of p27(Kip1) protein in serum-stimulated, ERK1/2-active cells was associated with increased levels of Skp2, an E3 ubiquitin ligase for p27(Kip1), whose knockdown by RNA interference induced p27(Kip1) expression. Further, forced expression of Skp2 in ERK1/2-inhibited cells downregulated p27(Kip1). Transcriptional upregulation of p27(Kip1) mRNA in ERK1/2-inhibited cells, demonstrated by real-time PCR, correlated with forkhead box O 3a (FOXO3a) transcription factor activation, shown by gel shift assay. FOXO3a knockdown attenuated p27(Kip1) mRNA and protein expression in ERK1/2-inhibited cells. We provide evidence for the first time that, in cardiac fibroblasts, activated ERK1/2 regulates p27(Kip1) expression transcriptionally and posttranslationally via FOXO3a- and Skp2-dependent mechanisms. Additionally, this study uncovers interesting interactions between critical cell cycle regulatory elements that are only beginning to be understood.
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    Model of cardiovascular injury in magnesium deficiency
    (MEDICAL HYPOTHESES, 2001)
    Magnesium deficiency is known to produce cardiovascular lesions. It is, however, not clear as to what constitutes magnesium deficiency - reduced serum levels, reduced tissue levels or reduced intracellular levels of the ionic form of the element. This article cites evidence in support of a hypothesis that a fall in serum magnesium levels may trigger a temporal sequence of events involving vasoconstriction, hemodynamic alterations and vascular endothelial injury to produce pro-inflammatory, pro-oxidant and pro-fibrogenic effects, resulting in initial perivascular myocardial fibrosis which, in turn, would cause myocardial damage and replacement fibrosis. Further, angiotensin II may be the prime mover of the pathogenetic cascade in magnesium deficiency. Importantly, such a mechanism of cardiovascular injury would be independent of a reduction in myocardial or vascular tissue levels of magnesium. (C) 2001 Harcourt Publishers Ltd.
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    Molecular basis and functional significance of Angiotensin II-induced increase in Discoidin Domain Receptor 2 gene expression in cardiac fibroblasts
    (JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2016) George, M; Vijayakumar, A; Dhanesh, SB; James, J; Shivakumar, K
    Delineation of mechanisms underlying the regulation of fibrosis-related genes in the heart is an important clinical goal as cardiac fibrosis is a major cause of myocardial dysfunction. This study probed the regulation of Discoidin Domain Receptor 2 (DDR2) gene expression and the regulatory links between Angiotensin II, DDR2 and collagen in Angiotensin II-stimulated cardiac fibroblasts. Real-time PCR and western blot analyses showed that Angiotensin II enhances DDR2 mRNA and protein expression in rat cardiac fibroblasts via NADPH oxidase-dependent reactive oxygen species induction. NF-kappa B activation, demonstrated by gel shift assay, abolition of DDR2 expression upon NF-kappa B inhibition, and luciferase and chromatin immunoprecipitation assays confirmed transcriptional control of DDR2 by NF-kappa B in Angiotensin II-treated cells. Inhibitors of Phospholipase C and Protein kinase C prevented Angiotensin II-dependent p38 MAPK phosphorylation that in turn blocked NF-kappa B activation. Angiotensin II also enhanced collagen gene expression. Importantly, the stimulatory effects of Angiotensin II on DDR2 and collagen were inter-dependent as siRNA-mediated silencing of one abolished the other. Angiotensin II promoted ERK1/2 phosphorylation whose inhibition attenuated Angiotensin II-stimulation of collagen but not DDR2. Furthermore, DDR2 knockdown prevented Angiotensin II-induced ERK1/2 phosphorylation, indicating that DDR2-dependent ERK1/2 activation enhances collagen expression in cells exposed to Angiotensin II. DDR2 knockdown was also associated with compromised wound healing response to Angiotensin II. To conclude, Angiotensin II promotes NF-kappa B activation that up-regulates DDR2 transcription. A reciprocal regulatory relationship between DDR2 and collagen, involving cross-talk between the GPCR and RTK pathways, is central to Angiotensin II-induced increase in collagen expression in cardiac fibroblasts. (C) 2015 Elsevier Ltd. All rights reserved.
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    Molecular mechanisms in H2O2-induced increase in AT1 receptor gene expression in cardiac fibroblasts: A role for endogenously generated Angiotensin II
    (JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2016) Anupama, V; George, M; Dhanesh, SB; Chandran, A; James, J; Shivakumar, K
    The AT1 receptor (AT1R) mediates the manifold actions of angiotensin II in the cardiovascular system. This study probed the molecular mechanisms that link altered redox status to AT1R expression in cardiac fibroblasts. Real-time PCR and western blot analysis showed that H2O2 enhances AT1R mRNA and protein expression via NADPH oxidase-dependent reactive oxygen species induction. Activation of NF-kappa B and AP-1, demonstrated by electrophoretic mobility shift assay, abolition of AT1R expression by their inhibitors, Bay-11-7085 and SR11302, respectively, and luciferase and chromatin immunoprecipitation assays confirmed transcriptional control of AT1R by NF-kappa B and AP-1 in H2O2-treated cells. Further, inhibition of ERK1/2, p38 MAPK and c-Jun N-terminal kinase (JNK) using chemical inhibitors or by RNA interference attenuated AT1R expression. Inhibition of the MAPKs showed that while ERK1/2 and p38 MAPK suffice for NF-kappa B activation, all three kinases are required for AP-1 activation. H2O2 also increased collagen type I mRNA and protein expression. Interestingly, the AT1R antagonist, candesartan, attenuated H2O2-stimulated AT1R and collagen mRNA and protein expression, suggesting that H2O2 up-regulates AT1R and collagen expression via local Angiotensin II generation, which was confirmed by real-time PCR and ELISA. To conclude, oxidative stress enhances AT1R gene expression in cardiac fibroblasts by a complex mechanism involving the redox-sensitive transcription factors NF-kappa B and AP-1 that are activated by the co-ordinated action of ERK1/2, p38 MAPK and JNK. Importantly, by causally linking oxidative stress to Angiotensin II and AT1R up-regulation in cardiac fibroblasts, this study offers a novel perspective on the pathogenesis of cardiovascular diseases associated with oxidative stress. (C) 2016 Elsevier Ltd. All rights reserved.
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    Pro-fibrogenic effects of magnesium deficiency in the cardiovascular system
    (MAGNESIUM RESEARCH, 2002)
    Magnesium deficiency is known to produce cardiovascular injury. A large body of experimental evidence supports the postulation that an immuno-inflammatory reaction and increased oxidative stress may damage the myocardium and vasculature in magnesium deficiency. Reparative/reactive fibrosis in response to the injury has, however, received little attention. Recent evidence from a rodent model of acute magnesium deficiency suggests that humoral factors may activate cardiac fibroblasts by a free radical-mediated mechanism and contribute to cardiac fibrogenesis. A similar mechanism may also promote cellular hyperplasia and increased matrix synthesis in the vasculature.
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    Superoxide-mediated activation of cardiac fibroblasts by serum factors in hypomagnesemia
    (FREE RADICAL BIOLOGY AND MEDICINE, 2001)
    Magnesium deficiency is known to produce myocardial fibrosis in different animal models, but the underlying mechanisms are unclear. However, circulating levels of pro-oxidant and mitogenic factors are reported to be elevated in a rodent model of acute magnesium deficiency, suggesting a role for humoral factors in the pathogenesis of the cardiovascular lesions. Probing the mechanism of cardiac fibrogenesis in magnesium deficiency, the present study furnished evidence that serum from magnesium-deficient rats has a more marked effect than serum from magnesium-sufficient rats on mitogenesis, net collagen production, and superoxide generation in cardiac fibroblasts from young adult rats. The enhanced mitogenic response was abolished by superoxide dismutase and N-acetyl cysteine, showing that it is mediated by superoxide anion. Further, a modest inhibitory effect of the neurokinin-1 receptor antagonist, spantide, suggested that factors acting via neurokinin-1 receptors may partly modulate cardiac fibroblast function in magnesium deficiency. The findings are consistent with the postulation that serum factors may activate cardiac fibroblasts via a superoxide-mediated mechanism and contribute to the fibrogenic response in the heart in magnesium deficiency. (C) 2001 Elsevier Science Inc.