Biomedical subjects

M T Subbiah

Publications and source records attributed to M T Subbiah.

At least 55 records · Page 3Linked to original sources

PubMed1987

Cholestyramine treatment in early life of low-density lipoprotein receptor deficient Watanabe rabbits: decreased aortic cholesteryl ester accumulation and atherosclerosis in adult life.

Effect of cholestyramine treatment in early life of Watanabe heritable hyperlipidemic rabbits (an animal model lacking low-density lipoprotein receptor activity) on subsequent (6 months recovery) occurrence of natural atherosclerotic lesion and arterial cholesterol metabolism was investigated. Initial cholestyramine treatment decreased both plasma total cholesterol and HDL-cholesterol levels which normalized within 4 weeks after treatment was discontinued. At 9 months of age (age of occurrence of spontaneous atherosclerotic lesions), the extent of aortic atherosclerosis in cholestyramine pre-treated animals was modestly lower (P less than 0.05), as compared to controls, with a significant (P less than 0.05) decrease in aortic cholesteryl ester content. Furthermore, at the end of the recovery period aortic activity of acyl-CoA: cholesterol acyltransferase and neutral cholesterol esterase activity was significantly (P less than 0.05) lower in cholestyramine-pretreated animals. These studies show that early cholestyramine pre-treatment in a low-density lipoprotein receptor-deficient animal model causes persistent changes which might influence cholesteryl ester accumulation and atherogenesis in adult life, even after cholestyramine treatment is discontinued.

Age Factors↗

PubMed1987

Cholestyramine treatment in early life. Immediate and delayed effects on arterial cholesteryl ester metabolizing enzymes in the rabbit.

Feeding of cholestyramine-enriched diet to weaned normocholesterolemic rabbits resulted in: lowering of plasma cholesterol and distinctly decreased activity of aortic acyl-CoA cholesterol acyl transferase with no changes in aortic acid and neutral cholesteryl esterase activity. At 9 weeks after cessation of cholestyramine treatment enhanced activity of both aortic esterases were noted despite normalization of plasma cholesterol. No evidence for the presence of plasma factor influencing esterases activity was found in lipoprotein-free serum from cholestyramine-treated animals. These studies show that cholestyramine treatment in early life causes immediate and delayed changes in rabbit arterial cholesteryl ester metabolizing enzymes.

Animals↗

PubMed1987

Studies on aorta during development. I. Fetal rabbit aorta under ex vivo and in vitro conditions: rapid changes in smooth muscle cell phenotype, cell proliferation and cholesterol content with organ culture.

The structural development of the already well defined fetal rabbit aortic wall from 22 to 31 days of gestation in vivo consists of increasing aortic wall thickness, elastic lamina continuities, extracellular matrix deposition, and maturing of the fine structure of the medial smooth muscle cells. In vivo at term (31 days), the mature aortic smooth muscle cells demonstrated the characteristic thin, thick and intermediate filaments, dense plaques, endoplasmic reticulum, golgi, plasmalemma vesicles and an incomplete basal lamina. The fetal aorta rapidly responded to organ culture with various changes. Fetal smooth muscle cells modified their phenotype to the synthetic state when cultured in both serum-supplemented and serum-free media. This smooth muscle cell modification occurred after 3 days of culture in fetal explants. The synthetic type smooth muscle cells (fetal) began to proliferate after 6 days of culture. This proliferation resulted in a peripheral outgrowth after 9 days of 10-20 layers in fetal cultures from serum-supplemented media and of 2-4 layers in serum-free media. The orderly arrangement of the internal elastic lamina and alternating medial layers of smooth muscle cells and elastic lamina seen in vivo was disrupted along with increased matrix after 9 days of fetal explant culture. Significant numbers of 'modified' synthetic phenotype smooth muscle cells were not observed in adult aortic explants until after 15 days in culture in serum supplemented media. The mature contractile phenotype smooth muscle cell predominated in adult explants cultured in serum-free media. Significant synthetic phenotype smooth muscle cell proliferation only occurred in adult explants after 15 days culture in serum-supplemented media. When compared to aorta in vivo evidence for increases in cholesterol esterification were observed in both fetal (9 days) and adult (15 days) explants cultured in both serum-supplemented and serum-free media. The fetal aorta in organ culture appeared to be more susceptible than the adult aorta to (a) phenotypic modulation of smooth muscle cells to the synthetic state, (b) smooth muscle cell proliferation, and (c) early cholesteryl ester accumulation.

Aging↗

PubMed1987

Studies on aorta during development. II. Differences in ontogeny of the key enzymes involved in cholesteryl ester synthesis and hydrolysis in rabbit aorta.

It is well known that cholesteryl ester accumulation is dramatically increased in the atherosclerotic artery. The enzymes acyl-CoA: cholesterol acyltransferase (ACAT), acid cholesteryl esterase (ACE) and neutral cholesteryl esterase (NCE) may play key roles in the accumulation of cholesteryl esters in the arterial wall. However, very little is known regarding the developmental pattern of the key enzymes involved in cholesteryl ester synthesis and hydrolysis. The total activities of ACAT, ACE and NCE were measured by radioassay using liposomal substrates in rabbit aortic homogenates. Our results indicate that ACAT activity decreases as a quadratic function with age (P less than 0.05). ACAT activity (pmol/100 mg protein/min) decreased from a high value in the fetus at term (63.3 +/- 7.4) to gradually lower values with increasing age. On the other hand, ACE activity (pmol/mg protein/min) was low in the fetus at term, and changed as a quadratic function with age (P less than 0.05) increasing gradually to higher activities with age up to a maximum at 12 weeks then decreased at 21 weeks. NCE activity (pmol/mg protein/min) increased dramatically from a low value in the fetus at term (3.34 +/- 0.48) to a maximum value at 1.5 weeks (14.65 +/- 2.73) then decreased as a linear function with increasing age up to 21 weeks (P less than 0.05). Plasma total cholesterol (mg/dl) also increased sharply from the fetal value at term of 98.5 +/- 5.2 to a maximum value at 1.5 weeks of 666.4 +/- 33.4, then decreased as a quadratic function with increasing age up to 21 weeks (40.8 +/- 6.7) (P less than 0.05). The free cholesterol content (microgram/mg protein) of the aortic tissue was initially high in the fetus (24.8 +/- 5.9) then increased with age. Examination of the ratio of synthesis to hydrolysis of cholesteryl esters as an index of enzyme activity units demonstrated a very high index in the fetus of 6.1 that rapidly decreased with increasing age in the young adult rabbit down to a value of 0.4 by 21 weeks of age. Correlation coefficients between enzyme activities, plasma cholesterol levels and aortic cholesterol levels indicated (a) a positive correlation of NCE activity with plasma cholesterol, (b) a negative correlation of NCE and ACE with aortic-cholesteryl ester content, and (c) no significant correlation of ACAT activity with either plasma cholesterol or aortic cholesterol content, indicating other factors are involved.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗

PubMed1987

Ontogeny of 6-keto-PGF1 alpha synthesis in rabbit aorta and the effect of premature weaning.

A systematic study of the ontogeny of aortic 6-ketoprostaglandin F1 alpha synthesis from birth to adult life and the effect of premature weaning on this process was investigated in rabbits. Prostacyclin (PGI2) synthesis by both endogenous and exogenous arachidonic acid and its relation to aortic arachidonic acid content was determined. It was found that 1) PGI2 synthesis from endogenous arachidonic acid increased with age, whereas 2) PGI2 synthesis from exogenous arachidonic acid decreased. This correlated with a decrease in the incorporation of [14C]arachidonic acid into phospholipids with age. Aortic arachidonic acid concentration did not change from birth until 3 wk of life but increased markedly by 5 wk of age. Premature weaning caused a decrease in the synthesis of aortic PGI2 and in aortic arachidonic acid concentration initially, but the changes did not persist in later life. These studies suggest that the utilization of exogenous arachidonic acid by aorta decreases after birth perhaps due to maturity of the enzyme systems that synthesize and utilize endogenous substrates.

6-Ketoprostaglandin F1 alpha↗

PubMed1987

Coffee extracts inhibit platelet aggregation in vivo and in vitro.

The effect of aqueous coffee extracts on platelet aggregation in humans (in vitro) and rabbits (both in vitro and in vivo) was investigated. Coffee extracts were found to have anti-aggregatory effects on in vitro platelet aggregation induced by ADP or arachidonate but not by collagen. Coffee extracts were also effective after intravenous administration in rabbits. The compound(s) responsible for these effects are water-soluble, heat-resistant, appeared to be different from salicylates, and might also be due to unidentified compounds besides nicotinic acid or known xanthines. Coffee extract and selected fractions decreased the conversion of [14C]-arachidonic acid to thromboxane B2 by the platelets. These studies show that coffee extracts contain compounds which are active in inhibiting platelet aggregation, a critical step involved in thrombosis and other vascular disorders.

Adenosine Diphosphate↗

PubMed1986

Human breast milk contains a factor which markedly stimulates aortic prostacyclin synthesis.

Human breast milk has been shown to contain a potent factor which markedly stimulates the synthesis of prostacyclin by rabbit aorta. The stimulatory effect of colostrum was modest when compared to mature milk. This factor appears to be protein in nature with a molecular weight of less than 10 000. The main site of action of the factor appears to be on the conversion of arachidonic acid into prostacyclin. This factor might have a role in the optimal development of prostacyclin synthetic pathways which are not fully developed at birth.

6-Ketoprostaglandin F1 alpha↗

PubMed1986

Human breast milk stimulates bile acid secretion by fetal rabbit liver in organ culture.

Fetal livers from rabbits at 30 days of gestation were grown in organ culture and the effect of human milk added to the culture medium on the ability of liver to excrete bile acids (cholylglycine) was examined. Human breast milk promoted a concentration related increase in cholylglycine accumulation in the medium. The factor(s) present in milk responsible for this effect appear to be non-protein in nature and is associated with the floating lipid fraction. Furthermore, milk enhances the integrity of liver explants, as established by light microscopy.

Animals↗

PubMed1985

Ontogeny of guinea pig liver cholesterol 7 alpha-hydroxylase: unexpected inverse correlation of enzyme activity with expanding bile acid pool.

Changes in the activity of guinea pig liver cholesterol 7 alpha-hydroxylase (rate limiting enzyme of cholesterol catabolism) from birth to adult life was investigated using a microsomal acetone extraction method (to remove endogenous cholesterol). Contrary to the previously held notion, it was noted that while the total bile acid pool increased progressively with age after birth, hepatic cholesterol 7 alpha-hydroxylase specific activity declined. Neonatal hepatic cholesterol 7 alpha-hydroxylase showed an increase in enzyme activity in response to cell supernatant factors (100,000 xg supernatant) from neonatal livers, but not from adult livers.

Age Factors↗

PubMed1985

High acyl-CoA cholesterol acyl transferase activity in fetal rabbit aorta: evidence for the presence of stimulating factor(s) in amniotic fluid.

The activity of Acyl CoA-cholesterol acyl transferase was markedly high in fetal aortas when compared to maternal and adult male rabbits. This activity dropped by 50% at 1 week of age. This high activity in fetal aorta a) did not appear to be due to changes in plasma cholesterol levels or to the later development of endogenous inhibitor in the aorta, but rather b) due to stimulatory factor(s) present in amniotic fluid.

Amniotic Fluid↗

PubMed1985

Human breast milk stimulates prostaglandin synthesis in cultured human skin fibroblasts.

Effect of human breast milk or its fractions on prostaglandin synthesis was investigated in cultured human skin fibroblasts. Prostaglandins released into the media were measured by radioimmunoassay. Incorporation of breast milk (2% level) into 10% fetal calf serum media (for 48 hours) stimulated the synthesis of 6-keto-PGF1 alpha (stable product of prostacyclin) by 800%. This stimulating effect of milk persisted after cold acetone extraction to remove phospholipids and potentiated further after dialysis. Stimulation by one of the commercial formulas (Similac) was less than 50% of the milk effect. Milk also stimulated PGE2 synthesis, although to a much lesser degree. These studies show for the first time that a) human breast milk contains potent factor(s) capable of influencing prostaglandin synthesis and suggest that b) these factors might have a role in the development of lipid synthetic pathways during early life.

6-Ketoprostaglandin F1 alpha↗

PubMed1985

Human breast milk stimulates rat liver cholesterol 7 alpha-hydroxylase activity in vitro.

Human breast milk at concentrations of (40 microliter/ml) markedly stimulates the activity of cholesterol 7 alpha-hydroxylase (rate limiting enzyme involved in cholesterol catabolism) in rat liver microsomal preparations. This activity persisted after a) cold acetone extraction (to remove cholesterol) b) dialysis and c) boiling and trypsin treatment of milk. Homogenized cow's milk and infant formula (Similac) also possessed the stimulating activity. These results suggest that milk might provide some factor(s) for the development of cholesterol catabolic process which is immature at birth.

Animals↗

PubMed1985

Human breast milk stimulates low density lipoprotein (LDL) binding to human skin fibroblasts in culture.

Human breast milk incorporated at 1% concentration into the culture medium significantly (p less than 0.05) increased the binding of 125I-LDL to receptors of human skin fibroblasts in culture. Homogenized cows milk and infant formula (Similac) also possessed this stimulating property. The stimulating activity of milk persisted after dialysis and extraction with cold acetone. These preliminary studies suggest that milk might contain potent factor(s) influencing cholesterol metabolic process in early life.

Cells, Cultured↗

PubMed1985

Response of normal and diabetic rat aorta to deendothelialization in terms of 6-keto-prostaglandin F1 alpha synthesis and cholesterol accumulation.

The response of rat aorta to balloon catheter-induced denudation in terms of 6-keto-PGF1 alpha synthesis and cholesterol accumulation was studied in normal and streptozotocin-induced diabetic animals. Initial studies in control rats showed that 1 day after deendothelialization, aortic 6-keto-PGF1 alpha was significantly reduced (31%), and this was normalized at 4 days after injury. However, endothelial regeneration as indicated by Evans blue staining was complete only at 14 days after denudation. Diabetic aorta showed a more severe reduction of 6-keto-PGF1 alpha production (50%) at 1 day after deendothelialization, but this was also normalized at 4 days after injury. Deendothelialization did not increase the accumulation of cholesterol in diabetic aorta. It is concluded that (a) recovery of PGI2 production in deendothelialized aorta does not parallel endothelial regeneration, indicating substantial contribution of subendothelial layer, in rats and (b) short-term aortic injury in diabetic rat will not influence the arterial repair process and cholesterol accumulation and is unlikely to be a contributing factor to increased atherogenesis.

6-Ketoprostaglandin F1 alpha↗

PubMed1985

Effect of glucocorticoid administration early in life on aortic prostaglandin synthesis and morphology in atherosclerosis-susceptible pigeons.

Effect of dexamethasone administration on aortic morphology, cholesterol content and synthesis of prostaglandins from (14C)-arachidonic acid in aorta of spontaneously atherosclerosis susceptible pigeons was examined. Dexamethasone markedly inhibited the synthesis of prostaglandin E2 and stimulated the synthesis of prostaglandin I2 in aorta. In aorta of glucocortocoid treated animals, endothelial abnormalities noted in control birds were decreased and numerous surface protrusions or 'microvilli' were noted. The possibility that glucocorticoid induced inhibition of PGE2 synthesis in pigeon aorta may contribute to improved aortic morphology is discussed.

6-Ketoprostaglandin F1 alpha↗

PubMed1985

Premature weaning-induced changes of cholesterol metabolism in guinea pigs.

Premature weaning in animals causes higher serum cholesterol levels and a relative inability to handle cholesterol challenge in adult life. The mechanisms responsible for these delayed effects of premature weaning are not clear. The aims of this investigation were to 1) determine the effect of premature weaning on the activity of hepatic cholesterol 7 alpha-hydroxylase and plasma cholesterol changes and 2) determine whether addition of cholesterol to the diet will restore premature weaning-induced changes. Premature weaning did not prevent the phenomenon of neonatal hypercholesterolemia noted in day 5 of normally weaned guinea pigs. At day 10, prematurely weaned animals had lower serum cholesterol when compared with normally weaned animals. Premature weaning caused (without or with cholesterol in diet) a significant decrease in the hepatic activity of cholesterol 7 alpha-hydroxylase, and this difference persisted (after 1 mo) when fed the stock diet. These studies demonstrate 1) premature weaning on day 2 does not prevent neonatal hypercholesterolemia on day 5, 2) premature weaning causes a decrease in hepatic cholesterol 7 alpha-hydroxylase activity that persists into adult life, and 3) dietary cholesterol intake in early life is unable to negate premature weaning-induced changes.

Aging↗

PubMed1985

Delayed effects of experimental maternal diabetes on plasma cholesterol level and vascular prostacyclin synthesis in the offspring.

The effect of streptozotocin-induced diabetes during pregnancy in rats on prostacyclin synthesis in aorta and heart of offsprings was investigated. Although the aortic and heart syntheses of 6-keto-PGF1 alpha in the offsprings of diabetic rats were not altered at birth, a significant rise in aorta and a decrease in the heart were evident at weaning. At weaning, offsprings of diabetic rats also show a significant rise in plasma cholesterol. These studies show that maternal diabetes might cause effects in the offspring which might become evident in later life.

6-Ketoprostaglandin F1 alpha↗

PubMed1984

Cholesterol 7 alpha-hydroxylase of rat liver: an insulin sensitive enzyme.

Four lines of evidence indicates that cholesterol-7 alpha-hydroxylase (ch-7 alpha-H, rate limiting enzyme of cholesterol catabolism) is an insulin sensitive enzyme. 1) Streptozotocin induced diabetes in the rat causes a marked increase in the hepatic activity of ch-7 alpha-H within 24 hrs. with no further increase in subsequent days. 2) Insulin injection can rapidly (within 24 hours) suppress the elevated enzyme activity to normal levels. 3) Insulin in vitro (0.02 U/ml) can directly suppress ch-7 alpha-H activity in isolated rat liver microsomes or in liver homogenates. 4) Upon exposure to insulin, microsomal ch-7 alpha-H activity showed a reduced stimulatory response to post-microsomal supernatant factors. These studies suggest that a) ch-7 alpha-H is an insulin sensitive enzyme and b) insulin might have a direct role in suppressing ch-7 alpha-H activity in rat liver.

Animals↗