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Biomedical subjects

S Goldfischer

Publications and source records attributed to S Goldfischer.

At least 55 records · Page 3Linked to original sources
PubMed1978

Hydrolase activities in the rat aorta. I. Effects of diabetes mellitus and insulin treatment.

Vascular disease in diabetics could arise in part from altered vessel wall catebolism. Specific activities of hydrolases in aortic smooth muscle cells from rats with streptozotocin-induced diabetes were measured. Enyzmes included: neutral alpha-glucosidase, alpha-mannosidase, and lysosomal N-acetyl beta-glucosaminidase, beta-galactosidase, cathepsin C, acid alpha-glucosidase, and acid cholesteryl esterase. After 4,8, and 11 weeks of diabetes, activities of all enzymes studied were decreased significantly in diabetic vessels, decreases ranging from 15% for cathepsin C to 62% for alpha-mannosidase. After 3 weeks of diabetes, insulin treatment for 1 week restored enzyme levels to normal. After 7 weeks of diabetes, 1 week of insulin treatment did not restore enzyme levels fully to normal (acid cholesteryl esterase was unchanged); 4 weeks of insulin did. Acid phosphatase and N-acetyl beta-glucosaminidase activities were reduced markedly in histochemical studies of diabetic aortas at all time periods and were restored by insulin treatment. Alloxan-induced diabetes gave results similar to those with streptozotocin. Significant decreases of aortic hydrolase activities, including those of lysosomes, occur in experimental diabetes mellitus and could contribute to accumulation of substrates in vascular smooth muscle cells.

Alloxan↗
PubMed1978

Hydrolase activities in the rat aorta. II. Effects of hypertension alone and in combination with diabetes mellitus.

Hypertension is an important risk factor for atherosclerosis and often occurs in association with diabetes mellitus. Specific activities of hydrolases in homogenates of aortas from rats with renal-clip hypertension, normotension following a period of hypertension, and hypertension combined with streptozotocin-induced diabetes mellitus were measured. Enzymes included: neutral alpha-glucosidase, and lysosomal N-acetyl-beta-glucosaminidase, beta-galactosidase, cathepsin C, acid alpha-glucosidase, and acid cholesteryl esterase. After 6 or 12 weeks of hypertension, specific activities of all enzymes measured were significantly increased, levels ranging from 24% above normal for cathepsin C to 351% above normal for N-acetyl-beta-glucosaminidase. Six weeks of normotension following 6 weeks of hypertension resulted in restoration to normal of four of the six enzyme activities; the remaining two enzymes were significantly below normal levels. Combined hypertension and diabetes mellitus showed smooth muscle cell levels of four of the five hydrolases measured to be significantly lower than those present with hypertension alone. In every instance, histochemical studies of aortas showed acid phosphatase and N-acetyl-beta-glucosaminidase activities which corresponded to the biochemical findings. These findings indicate profound and discrete effects of two clinical risk factors on vascular smooth muscle cell lysosomes.

Animals↗
PubMed1977

Intralysosomal lipid in long-term maintenance transplant atherosclerosis.

Intralysosomal accumulation of lipid has been implicated as an important mechanism in the pathogenesis of atherosclerosis. Although atherosclerosis develops frequently in organ transplants maintained on a long-term basis, to our knowledge no studies to date have demonstrated the intracellular localization of the lipid in this setting. Light and electron microscopic study of a renal artery branch from a transplanted kidney maintained for 3 1/2 years demonstrates that the lipid is sequestered within intimal smooth muscle cell lysosomes. The features of the atherosclerotic plaque in long-term transplantation appear to be identical to spontaneous lesions or those induced experimentally.

Arteriosclerosis↗
PubMed1976

Lipid accumulation in human aortic smooth muscle cell lysosomes.

Lipid deposition is a central feature of the human atherosclerotic lesion. Deficient lysosomal lipolytic activity has been implicated as a pathogenetic factor in atheroma formation. Cytochemical and ultrastructural examination of the abdominal aortas of 2 normal young males, ages 11 and 23, demonstrates lipid accumulation with lysosomes of intact mural smooth muscle cells. This appears to be an early stage in the process which eventually results in an overloading of lysosomes and the formation of lipid-laden foam cells.

Adult↗
PubMed1976

Endocytosis by vascular smooth muscle cells in vivo and in vitro. Roles or vesicles and lysosomes.

Overloading of lysosomes of smooth muscle cells with excess substrate may be a key event in the development of hypertensive and atherosclerotic vascular disease. Cellular uptake of materials and its relation to lysosomal function were studied by ultrastructural cytochemistry in aortic smooth muscle cells grown in vitro and in the intact animal. Injection of horseradish peroxidase (HRP) into hypertensive rats resulted in rapid insudation of the material into the environs of medial smooth muscle cells, entrance into surface pinocytic vesicles, and transport via vesicles into the cell interior where material was seen to accumulate within lysosomes. In vitro exposure of calf aortic cells to HRP in the medium resulted in a similar sequence of events. Pinocytic vesicles, seen both in vitro and in vivo, ranged in diameter from 650-1000 A. These dimensions are adequate to permit incorporation of intact lipoproteins of all classes, except the larger chylomicrons.

Animals↗
PubMed1976

Hypophosphatasia: a cytochemical study of phosphatase activities.

Skeletal abnormalities with defective formation of mature calcified bone are the most prominent clinical features of hypophosphatasia. Low concentrations of serum and tissue alkaline phosphatase and elevated plasma and urinary levels of phosphorylethanolamine (PEA) are also present. Although PEA is hydrolyzed by serum alkaline phosphatase, the relationship between PEA and the deficiency is unclear. PEA has not previously been tested as a cytochemical substrate for the in situ demonstration of human alkaline phosphatase activity. We have studied alkaline phosphatase activity in hypophosphatasia in tissue sections, utilizing PEA and adenosinetriphosphate (ATP) as well as the usual beta-glycerophosphate and naphthol phosphate substrates. Neutral and acid phosphatase activities were also examined. Our results demonstrate that PEA is a substrate for the localization of alkaline phosphatase in normal human tissue, but is not hydrolyzed in hypophosphatasia in the liver, brain or costochondral junction under alkaline conditions. In the kidney in hypophosphatasia only the straight segments of proximal tubules that rim the medullary rays are reactive with PEA. Similar results in hypophosphatasia were obtained at an alkaline pH with ATP, beta-glycerophosphate, and naphthol phosphate. However, the defect in hypophosphatasia is not a generalized deficiency of membrane-associated phosphatases because membranes that were deficient in alkaline phosphatase activity demonstrated normal reactivity with ATP at neutral pH. In addition, thiamine pyrophosphate was also split by Golgi membranes within the cytoplasm. Acid hydrolysis of beta-glycerophosphate by lysosomes was normal.

Alkaline Phosphatase↗
PubMed1976

Heavy metals and lysosomes.

Much can be gained by reassessing the processes which determine the ability of lysosomes to take up or exclude, sequester and mobilize heavy metals. To achieve a better understanding of these events, the chemical forms, intracellular pathways and modes of delivery of metals to lysosomes, as well as the specific physiologic ligands and molecular targets susceptible to metal toxicity have to be identified. None of these can be derived from measurements of metal contents of whole lysosomal fractions because the metal's "effective concentration" at a specific target site may be affected by the binding properties of the lysosomal ligand as well as by those of cation carrier proteins present in the cytosol (e.g., metallothionein), and by interactions with and competitions by other cellular organelles. Therefore, the possibility of such events diminishing or enhancing a metal's direct effect observable in in vitro systems has to be considered before extrapolating to the in vivo situation. Another pitfall to be wary of is the equation of an organelle's relative affinity for a metal in vitro with its susceptibility to the metal's toxic effects. This is evident, albeit at a tissue level rather than at that of organelles, from the discordance between the low affinity of nervous tissue for lead and this metal's pronounced encephalopathic effect. The answers to some of the questions raised in this review may possibly lead to pharmacologic applications, particularly to the development of effective agents for the removal from or the inactivation of toxic metals deposited in lysosomes. At present, considerable uncertainty exists regarding the possible interaction of therapeutic chelating agents with lysosomes in vivo. We do not know, for example, whether the contrasts between the remarkable effectiveness of penicillamine in mobilizing copper from tissues and the limited effectiveness of desferioxamine in removing excess iron stores can be accounted for by differences in accessibility of these two chelators to lysosomes. Or, alternatively, can these differences in effectiveness be related to different ligands or macromolecules interacting with each metal? At least part of the lysosomal iron is bound to ferritin molecules which may not be susceptible to the action of chelating agents after incorporation. Such speculation is not without foundation since ferritin molecules are heterogeneous. However, whether this heterogeneity, which is reflected in different organ-specific patterns of distribution (Powell et al. 1973), is the result of differing affinities of the isoferritins for specific subcellular organelles has not been established. It is conceivable that ferritin molecules present in the cytoplasm may be subtly different from those taken up by lysosomes, implying that the latter are endowed with capabilities for selection of specific macromolecules...

Animals↗
PubMed1975

Lysosomes and the sclerotic arterial lesion in Hurler's disease.

A case of Hurler's disease in a mentally retarded, six year old boy is reported. In Hurler's disease a lysosomal hydrolase, l-iduronidase, is deficient, and consequently undegradable mucopolysaccharide accumulates within lysosomes in many tissues. Severe occlusive coronary artery disease and sclerotic aortic lesions are common in very young patients, although their serum lipid and blood pressure levels are normal. Vascular collagen and elastin is increased, but little or no stainable lipid is present. Electron microscopy shows that aortic smooth muscle cells are distended by vacuoles, appearing empty in formalin fixed tissues, that identify them as the "gargoyle" cells in the proliferative lesion. The presence of a basic lysosomal defect and the absence of other contributing metabolic factors suggest that accumulation of an excess of undegradable substrate within smooth muscle lysosomes may be an initiating event in the development of proliferative sclerotic vascular lesions.

Aorta↗
PubMed1975

Arterial lysosomes and connective tissue in primate atherosclerosis and hypertension.

The cellular events that occur in the vessel wall consequent to changes in endothelial permeability result in the progression of vascular disease, particularly atherosclerosis. Female rhesus monkeys were fed an atherogenic diet or were made hypertensive for 6-8 months; and their vessels were then compared with vessels from control monkeys. Length-defined segments of coronary vessels, the thoracic aorta, and the abdominal aorta showed significant increases in total connective tissue in the atherosclerotic and hypertensive groups; pulmonary vessels did not. The diseased aortic segments had increased levels of two lysosomal enzymes, acid phosphatase and beta-N-acetylglucosaminidase; pulmonary vessels were not diseased and did not show these changes. Coronary vessels from the atherosclerotic and hypertensive groups did not show an increase in enzyme levels on biochemical measurements, but focal accumulations of lysosomes were identified by cytochemical techniques. In atherosclerotic lesions, a doubling of cholesterol and more than a tenfold increase in cholesterol ester were found. These connective tissue and lysosomal changes are early features of primate vascular disease and may result from the accumulation of excessive substrate (cholesterol ester) in the lysosomes of vascular smooth muscle cells.

Acid Phosphatase↗
PubMed1975

Lipid accumulation in smooth muscle cell lysosomes im primate atherosclerosis.

Cytochemical and ultrastructural examination of the developing atherosclerotic lesion in hypercholesterolemic rhesus monkeys reveals that lipid is sequestered within lysosomes of aortic smooth muscle cells. A common pathway in the development of sclerotic arterial disease appears to be overloading of vascular smooth muscle cell lysosomes with a variety of metabolites. This may occur as a consequence of an excess of substrate or because of a congenital deficiency of a lysosomal hydrolase.

Animals↗
PubMed1973

Peroxisomal and mitochondrial defects in the cerebro-hepato-renal syndrome.

The cerebro-hepato-renal syndrome is a rare familial malady with cerebral, renal, and skeletal abnormalities, severe hypotonia, cirrhosis, iron and lipid storage, and death within 6 months. Correlated electron microscopic, histochemical, and biochemical studies demonstrate defects in two oxidative organelles. Peroxisomes cannot be found in hepatocytes and renal proximal tubules. In hepatocytes and cortical astrocytes, mitochondria are distorted in their appearance and glycogen stores are increased. Oxygen consumnption of brain and liver mitochondrial preparations with succinate and with substrates reducing nicotinamide adenine dinucleotide is markedly diminished, but the consumption is normal with ascorbate and tetramethylphenylenediamine, which suggests a defect in electron transport prior to the cytochromes. Histochemical studies of mitochondrial oxidation point to a defect between the succinate dehydrogenase flavoprotein and coenzyme Q, possibly in the region of nonheme iron protein.

Acidosis↗