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Biomedical subjects

K Shivakumar

Publications and source records attributed to K Shivakumar.

At least 19 recordsLinked to original sources
PubMed2006

Cardiac fibrogenesis in magnesium deficiency: a role for circulating angiotensin II and aldosterone.

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 [3H]thymidine and [3H]proline incorporation into cardiac fibroblasts from young adult rats were evaluated in the presence of losartan, an angiotensin II type 1 (AT1) 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.

Aldosterone↗
PubMed2006

Human protein reference database--2006 update.

Human Protein Reference Database (HPRD) (http://www.hprd.org) was developed to serve as a comprehensive collection of protein features, post-translational modifications (PTMs) and protein-protein interactions. Since the original report, this database has increased to >20 000 proteins entries and has become the largest database for literature-derived protein-protein interactions (>30 000) and PTMs (>8000) for human proteins. We have also introduced several new features in HPRD including: (i) protein isoforms, (ii) enhanced search options, (iii) linking of pathway annotations and (iv) integration of a novel browser, GenProt Viewer (http://www.genprot.org), developed by us that allows integration of genomic and proteomic information. With the continued support and active participation by the biomedical community, we expect HPRD to become a unique source of curated information for the human proteome and spur biomedical discoveries based on integration of genomic, transcriptomic and proteomic data.

Databases, Protein↗
PubMed2002

Differential response of cardiac fibroblasts from young adult and senescent rats to ANG II.

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.

Aging↗
PubMed2002

Calcium- and superoxide anion-mediated mitogenic action of substance P on cardiac fibroblasts.

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 micromol/l. It elicited no change in net collagen production, total protein synthesis, or cell protein content but increased (45)Ca 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 Ca(2+) 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 Ca(2+) homeostasis may act in concert to mediate its mitogenic action.

Acetylcysteine↗
PubMed2002

Pro-fibrogenic effects of magnesium deficiency in the cardiovascular system.

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.

Cardiomyopathies↗
PubMed2001

Superoxide-mediated activation of cardiac fibroblasts by serum factors in hypomagnesemia.

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.

Animals↗
PubMed2001

L-type calcium channel blockers and EGTA enhance superoxide production in cardiac fibroblasts.

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.

Animals↗
PubMed2001

Model of cardiovascular injury in magnesium deficiency.

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.

Cardiovascular Diseases↗
PubMed1999

Molecular structures and conformations of three 3-azabicyclononanes.

The structure, conformation, molecular geometry and the mode of packing of 7-tert-butyl-N-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonane (C(25)H(33)N; MTABN), N-acetyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonane (C(22)H(25)NO; AABN) and N-methyl-2,4-bis(2-methylphenyl)-3-azabicyclo[3.3.1]nonan-9-ol (C(23)H(29)NO; MHABN) are presented. The compounds MTABN and MHABN crystallize in monoclinic space groups, whereas AABN is orthorhombic. In each of the three structures, the bicyclic ring system adopts a chair-chair conformation and the phenyl rings are in equatorial orientation with respect to the piperidine ring. In AABN, apart from the van der Waals forces, weak intermolecular C-H.O type interactions are involved in the packing.

Journal Article↗
PubMed1998

Alterations in collagen metabolism and increased fibroproliferation in the heart in cerium-treated rats: implications for the pathogenesis of endomyocardial fibrosis.

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.

Animals↗
PubMed1997

Magnesium deficiency-related changes in lipid peroxidation and collagen metabolism in vivo in rat heart.

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 [3H]-proline and [3H]-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.

Animals↗
PubMed1997

Magnesium deficiency enhances oxidative stress and collagen synthesis in vivo in the aorta of rats.

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 was 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 [3H]-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.

Animals↗
PubMed1995

Cerium stimulates protein biosynthesis in rat heart in vivo.

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 (3H)-phenylalanine and (3H)-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.

Animals↗
PubMed1992

Paradoxical effect of cerium on collagen synthesis in cardiac fibroblasts.

The present study examined the effect of cerium on collagen synthesis in cultured cardiac fibroblasts and explants. At 100 nM, a concentration comparable with that found in the cardiac tissue of patients with endomyocardial fibrosis, the element was found to enhance the incorporation of tritiated proline into collagen and non-collagen proteins while at 10 microM, it had an inhibitory effect. Cerium was found to have no effect on rates of DNA synthesis in fibroblasts at 100 nM. However, at this concentration, the element markedly enhanced the incorporation of tritiated uridine into RNA, suggesting that cerium may act at the level of transcription to stimulate collagen and non-collagen protein syntheses. The stimulatory action of very low levels of cerium on collagen synthesis may contribute to the accumulation of collagen seen in endomyocardial fibrosis.

Animals↗
PubMed1991

Cerium depresses protein synthesis in cultured cardiac myocytes and lung fibroblasts.

The present study examined the effect of Cerium on protein synthesis in cultured cardiac myocytes and lung fibroblasts exposed to normal and markedly subnormal levels of Mg2+. Cerium was found to have a general inhibitory effect on protein synthesis in these cell types, including the synthesis of myofibrillar proteins in the cardiac myocytes. Further, the effect of the metal ion was more pronounced in cells exposed to the Mg2(+)-deficient medium. The possible implications of the observations are discussed.

Animals↗
PubMed1989

Synthetic hydrogel microspheres as substrata for cell adhesion and growth.

Cross-linked poly(methyl methacrylate) (PMMA) microspheres were subjected to alkaline hydrolysis to obtain hydrophilic microspheres having carboxyl residues distributed throughout the matrix. These microspheres were found to support the growth of human skin fibroblasts and human heart and lung cells. Further, fibroblasts grown on them were found to be comparable with those grown on the commercial tissue culture plate with respect to [14C]amino acid uptake and incorporation into proteins. The hydrolyzed PMMA microspheres may find application as a microcarrier for cell culture.

Cell Adhesion↗
PubMed1989

Interactions of thorium and cerium with adenine nucleotides.

The present study demonstrates an effect of the actinide, Thorium (Th), and the lanthanide, Cerium (Ce), on the non-enzymatic hydrolysis of adenine and guanine nucleotides. Thorium was found to be a more effective catalyst of the reaction than Cerium. Further, both the elements promoted the binding of Creatine kinase (CK) to Cibacron blue F3 GA, the substrate analogue of the enzyme, even in the absence of Mg2+, the physiological cofactor. These observations imply that toxic heavy metals can mimic the functional effects of the essential elements despite differences in their physicochemical properties.

Adenine Nucleotides↗