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M C Kowala

Publications and source records attributed to M C Kowala.

16 recordsLinked to original sources
PubMed1997

Stimulation of activin A expression in rat aortic smooth muscle cells by thrombin and angiotensin II correlates with neointimal formation in vivo.

Vasoactive GTP-binding protein-coupled receptor agonists (e.g., angiotensin II [AII] and alpha-thrombin) stimulate the production of mitogenic factors from vascular smooth muscle cells. In experiments to identify mitogens secreted from AII- or alpha-thrombin-stimulated rat aortic smooth muscle (RASM) cells, neutralizing antibodies directed against several growth factors (e.g., PDGF and basic fibroblast growth factor [basic FGF]) failed to inhibit the mitogenic activity of conditioned media samples derived from the cells. In this report, we found that polyclonal neutralizing antibodies directed against purified human placental basic FGF reduced the mitogenic activity of AII-stimulated RASM cell-conditioned media and in immunoblot experiments identified a 26-kD protein (14 kD under reducing conditions) that was distinct from basic FGF. After purification from RASM cell-conditioned medium, amino acid sequence analysis identified the protein as activin A, a member of the TGF-beta superfamily. Increased activin A expression was observed after treatment of the RASM cells with AII, alpha-thrombin, and the protein kinase C agonist PMA. In contrast, PDGF-BB or serum caused only a minor induction of this protein. Although activin A alone only weakly stimulated RASM cell DNA synthesis, it demonstrated a potent comitogenic effect in combination with either EGF or heparin-binding EGF-like growth factor in the RASM cells, increasing DNA synthesis by up to fourfold. Furthermore, in a rat carotid injury model, activin A mRNA was upregulated within 6 h after injury followed by increases in immunoreactive protein detected in the expanding neointima 7 and 14 d later. Taken together, these results indicate that activin A is a vascular smooth muscle cell-derived factor induced by vasoactive agonists that may, either alone or in combination with other vascular derived growth factors, have a role in neointimal formation after arterial injury.

Activins↗
PubMed1995

Regression of early atherosclerosis in hyperlipidemic hamsters induced by fosinopril and captopril.

We determined whether inhibiting angiotensin-converting enzyme (ACE) with fosinopril or captopril induced the regression of atherosclerosis in hamsters. A pressor experiment demonstrated that 100 mg/kg fosinopril or captopril almost completely inhibited ACE activity in vivo. Another study established that feeding hamsters 0.05% cholesterol and 10% coconut oil resulted in rapid and progressive accumulation of oil red O-stained macrophage-foam cells in the aortic arch. In the regression study, three groups of hamsters were fed the same atherogenic diet for 4 weeks to induce fatty lesions in the arch. After 4 weeks, plasma lipids, blood pressure (BP), and atherosclerosis were quantified in control hamsters. Beginning at 4 weeks, the two remaining groups of hamsters were treated with 100 mg/kg/day fosinopril or 100 mg/kg/day captopril for 6 more weeks while receiving the atherogenic diet. After 6-week treatment, plasma lipids, BP, and atherosclerosis were quantified in the two treated groups (i.e., study week 10), and they were compared with the 4-week controls. As compared with that in controls, fosinopril decreased plasma low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterols by approximately 69%. High density lipoprotein (HDL) cholesterol decreased by 16% and total triglycerides decreased by 56% as compared with that of controls. Captopril did not alter LDL plus VLDL cholesterols or total triglycerides, but HDL cholesterol decreased by 24% as compared with that of the control group. As compared with that of control hamsters, mean arterial BP (MAP) decreased by 9% with captopril treatment, and heart rate (HR) was decreased by both fosinopril and captopril.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1995

Selective blockade of the endothelin subtype A receptor decreases early atherosclerosis in hamsters fed cholesterol.

Recent studies suggest that endothelin and its receptors may be involved in atherogenesis. To test this hypothesis, cholesterol-fed hamsters were treated with a selective endothelin subtype A (ETA) receptor antagonist BMS-182874. Characterization of hamster atherosclerotic plaques indicated that they contained a fibrous cap of smooth muscle cells, large macrophage-foam cells, and epitopes of oxidized low density lipoprotein. Messenger RNA for both ETA and ETB receptors was detected in aortic endothelial cells, in medial smooth muscle cells, and in macrophage-foam cells and smooth muscle cells of the fibro-fatty plaques. BMS-182874 inhibited the endothelin-1-induced pressor response whereas the depressor effect was unaltered, suggesting that vascular ETA receptors were selectively blocked in vivo. In hyperlipidemic hamsters, BMS-182874 decreased the area of the fatty streak by reducing the number and size of macrophage-foam cells. The results indicated that ETA receptors and thus endothelin promoted the early inflammatory phase of atherosclerosis.

Animals↗
PubMed1994

Inhibitors of angiotensin converting enzyme decrease early atherosclerosis in hyperlipidemic hamsters. Fosinopril reduces plasma cholesterol and captopril inhibits macrophage-foam cell accumulation independently of blood pressure and plasma lipids.

The effect of two angiotensin converting enzyme (ACE) inhibitors on the development of atherosclerosis was determined in hyperlipidemic hamsters. Preliminary studies indicated that only fosinopril (50 mg/kg) temporarily decreased mean arterial pressure, while after chronic dosing fosinopril and captopril (50 mg/kg) were ineffective. The same dose of fosinopril and captopril inhibited the angiotensin I pressor response, indicating these agents suppressed ACE activity in vivo. In the 3 week atherosclerosis experiment, all hamsters were fed chow supplemented with 0.05% cholesterol and 10% coconut oil. Control hamsters were compared with those receiving either 50 mg/kg per day of fosinopril or 50 mg/kg per day of captopril. After 3 weeks, fosinopril reduced plasma total cholesterol, low density lipoprotein (LDL) plus very low density lipoprotein cholesterol and total triglycerides by 17%, 27% and 45%, respectively. Captopril only reduced high density lipoprotein cholesterol by 20%. Neither fosinopril or captopril altered blood pressure at 3 weeks. Atherosclerosis was quantified from en face preparations of the lesion-prone aortic arch that were stained with oil red O (for cholesteryl ester and triglycerides). In control hamsters, oil red O labeled numerous subendothelial macrophage-foam cells located along the inner curvature of the aortic arch. Compared with controls, fosinopril reduced the number of intimal macrophage-foam cells/mm2, foam cell size and the fatty streak area by 85%, 38% and 90%, respectively. Captopril decreased these parameters by 44%, 16% and 53%. Thus captopril decreased early atherosclerosis without affecting plasma LDL cholesterol or blood pressure, which suggested that inhibiting ACE (or kininase II) directly impeded the accumulation and formation of macrophage-foam cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Prostacyclin agonists reduce early atherosclerosis in hyperlipidemic hamsters. Octimibate and BMY 42393 suppress monocyte chemotaxis, macrophage cholesteryl ester accumulation, scavenger receptor activity, and tumor necrosis factor production.

We determined the effects of two prostacyclin agonists (octimibate and BMY 42393) on the progression of the fatty streak in vivo and on macrophage function in vitro. Hamsters were fed chow plus 0.05% cholesterol and 10% coconut oil. Control hamsters were compared with animals receiving either octimibate (10 or 30 mg/kg per day) or BMY 42393 (30 mg/kg per day). After 10 weeks of treatment, octimibate decreased plasma total cholesterol and triglycerides by 43% and 32%, respectively. Neither agonist affected blood pressure or heart rate. Lesion-prone aortic arches were stained with hematoxylin and oil red O and examined en face. Compared with controls, octimibate and BMY 42393 on average decreased mononuclear cells attached to the luminal surface by 44% and reduced subendothelial macrophage-foam cell number by 56%, foam cell size by 38%, and fatty streak area by 63%. Since octimibate is a putative inhibitor of acyl coenzyme A cholesterol acyltransferase, we studied the effect of both agents on cholesteryl ester metabolism in murine macrophages. At 10 microM, octimibate and BMY 42393 decreased cholesteryl ester accumulation in macrophages by 90% and 41%, respectively. Octimibate inhibited cholesteryl ester synthesis by 96% and increased the rate of cholesteryl ester degradation by 52%. Both prostacyclin agonists reduced macrophage scavenger receptor-mediated uptake of acetylated low density lipoprotein by 24-66% and increased cyclic adenosine monophosphate levels. Octimibate and BMY 42393 inhibited the secretion of tumor necrosis factor by 80-88% when macrophages were activated with lipopolysaccharide. At 10 microM, both agents decreased human monocyte chemotaxis to N-formyl-methionyl-leucyl-phenylalanine by 64-79%. The in vitro results with octimibate and BMY 42393 are consistent with the low number of small foam cells quantified in vivo. We suggest that octimibate and BMY 42393 suppress monocyte-macrophage atherogenic activity and cytokine production and thus inhibit the development of early atherosclerosis.

Animals↗
PubMed1991

Doxazosin and cholestyramine similarly decrease fatty streak formation in the aortic arch of hyperlipidemic hamsters.

The effect of doxazosin, an alpha-1 adrenergic inhibitor, on atherosclerosis was determined in hyperlipidemic hamsters. Control hamsters fed chow plus 0.05% cholesterol and 10% coconut oil were compared to chow baseline animals, and to those receiving either 10 mg/kg/day doxazosin, or 245 mg/kg/day cholestyramine in the atherogenic diet. During 8 weeks of treatment, plasma lipids, mean arterial pressure (MAP) and heart rate (HR) were measured, then the ascending aortic arch was examined en face. Numbers of subendothelial macrophage-foam cells/mm2 and their average size (microns 2) were determined, and Oil red O staining (micrograms ORO/mm2) was quantitated to estimate lipid accumulation. Ultracentrifugation of control plasma demonstrate that low density lipoprotein (LDL) carried most of the cholesterol, and very low density lipoprotein (VLDL) was rich in triglycerides. Compared to controls, doxazosin and cholestyramine similarly decreased plasma total and LDL plus VLDL cholesterols, and total triglycerides on average by 46%, 61% and 45% respectively. High density lipoprotein cholesterol was unchanged. Doxazosin also reduced MAP by 18% without affecting HR. In all hamsters, foam cells and lipid accumulated in a lesion-prone area characterized by elevated endothelial cell density, and a thick intima of basement membrane-like material layered over "pads" of smooth muscle cells. Compared to controls, doxazosin and cholestyramine uniformly reduced the number of foam cells/mm2, foam cell size and ORO staining on average by 66%, 29% and 56%, respectively. We conclude that doxazosin decreases plasma lipids and inhibits the development of the fatty streak to a similar level as cholestyramine treatment.

Adrenergic alpha-Antagonists↗
PubMed1989

Effects of prazosin on hemodynamics, hemostasis, and serum lipid and lipoprotein levels in normal and hypercholesterolemic monkeys.

The effect of prazosin on hemodynamics, hemostasis, and serum lipid and lipoprotein levels was investigated in normal and hypercholesterolemic rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) monkeys. Administration of prazosin (2 mg/kg bodyweight, orally, twice a day) for three weeks caused significant reductions in plasma cholesterol, including low- plus very low-density lipoprotein cholesterol, apolipoprotein B, and triglyceride levels. Drug therapy was associated with increased high-density lipoprotein cholesterol levels, although in one group of monkeys this rise also was associated with a reduction in apolipoprotein A1. Prazosin treatment significantly decreased mean arterial pressure in normal and hypercholesterolemic monkeys. As was expected, acute administration of phenylephrine caused mean arterial pressure to rise, with animals receiving normal- or high-cholesterol-containing diets showing similar responses. After prazosin treatment, however, a greater inhibition in the phenylephrine pressor response was observed in hypercholesterolemic monkeys compared with normal animals. Platelet aggregation in response to adenosine 5'-diphosphate, prothrombin time, and activated partial thromboplastin time were not altered by prazosin. Thus, in our nonhuman primate models of hypercholesterolemia, administration of prazosin resulted in reduction in lipid and apoprotein levels with no change in hemostasis.

Animals↗
PubMed1989

Serum lipids, lipoproteins, hemodynamics, and hemostasis in doxazosin-treated monkeys.

The effect of doxazosin administration on hemodynamics, hemostasis, and serum lipid and lipoprotein levels was investigated in cynomolgus monkeys (Macaca fascicularis) with diet-induced hypercholesterolemia. Acute administration of doxazosin (1 and 5 mg/kg) reduced resting mean arterial pressure by 20% without affecting heart rate, and completely inhibited the pressor response to phenylephrine. Platelet aggregation, prothrombin time, and activated partial thromboplastin time were not altered by the drug. Long-term doxazosin administration (1, 10, and 20 mg/kg/day) was associated with significant reductions in levels of total serum cholesterol (13%), very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterol (14%), and apolipoprotein B (15%) without any significant effects on high-density lipoprotein (HDL) cholesterol and apolipoprotein A-1. A 76% reduction in serum triglycerides, independent of drug level, was also seen in doxazosin-treated monkeys. In monkeys removed from drug treatment, serum cholesterol initially exceeded and then returned to pretreatment levels, whereas serum triglycerides remained low for 3 weeks. In our hypercholesterolemic monkey model, the administration of doxazosin resulted in beneficial changes in lipid and apolipoprotein profiles, hemostasis, and hemodynamics.

Adrenergic alpha-Antagonists↗
PubMed1989

Effect of doxazosin on plasma lipids and atherogenesis: a preliminary report.

Chronic treatment with selective alpha 1-inhibitors has a beneficial impact on plasma lipids and arterial pressure. To study the effect of selective alpha 1-inhibition on atherogenesis, gerbils and hamsters were fed rodent chow containing 0.2% cholesterol and 10% coconut oil (by weight). One group of each species received the selective alpha 1-inhibitor doxazosin (gerbil, 17 mg/kg/day; hamster, 11 mg/kg/day) in the diet. In gerbils treated for 6 weeks with doxazosin, plasma total cholesterol fell by 39% and very-low-density lipoprotein (VLDL) plus low-density lipoprotein (LDL) cholesterol by 52% compared with control levels. Plasma triglyceride and high-density lipoprotein (HDL) cholesterol were unaffected. In hamsters treated with doxazosin for 6 weeks, plasma total cholesterol, VLDL plus LDL cholesterols, and triglyceride were reduced by approximately 40% compared with hyperlipidemic controls. HDL cholesterol, mean arterial pressure, and heart rate were not significantly altered. Using en face preparations of the hamster aortic arch, intimal macrophage-derived foam cells were quantitated. Compared with controls, doxazosin reduced the number of intimal foam cells/mm2 by 71%. We suggest that selective alpha 1-inhibition reduces foam cell accumulation by lowering plasma lipids and/or by a direct effect on the arterial wall.

Adrenergic alpha-Antagonists↗
PubMed1989

Low density lipoprotein heterogeneity in the cebus monkey.

In studies of cebus monkey plasma lipoproteins, we have used an ultracentrifugally generated density gradient to isolate two distinct species of low density lipoproteins (LDL). Compositional analyses revealed that each of the ultracentrifugally isolated fractions was enriched in cholesteryl esters and contained a single apolipoprotein which in terms of its mobility on SDS gels corresponded to apolipoprotein B-100, the major apolipoprotein of human LDL. Hydrodynamic measurements carried out in the analytical ultracentrifuge showed that F1.20 values were 30.0 for LDL1 and 23.5 for LDL2. In a solution of density 1.0069 g/ml, the sedimentation rates were 5.9 and 7.2 S for LDL1 and LDL2, respectively. In addition to sedimentation velocity data, we describe a new approach for using these same data to obtain calculated values for molecular weight. The hydrated densities calculated for the two fractions were 1.033 and 1.045 g/ml and calculated molecular weights were 3.08 million for LDL1 and 2.42 million for LDL2. Hydrated density values were in excellent agreement with those calculated from compositional data. Electron microscopy data showed that LDL1 had a larger mean diameter of 26.7 nm than LDL2 which had a diameter of 19.3 nm. Native gel electrophoretic analyses of the two LDL fractions in 3.5% acrylamide showed that, consistent with its size, LDL1 had slower mobility than LDL2.

Animals↗
PubMed1988

Intimal changes in the aorta of prehypertensive rats.

Intimal changes were quantitated in several rat models of arterial hypertension. One kidney-one clip rats drinking water (1K-1C-water), one-kidney rats treated with deoxycorticosterone acetate and drinking 1% NaCl (1K-DOCA-salt), and two-kidney rats drinking 1% NaCl (2K-salt) were studied after 1 to 8 weeks. The thoracic aorta was examined en face and by electron microscopy. Surprisingly, all 2K-salt, most 1K-DOCA-salt (17 out of 19), and two-thirds of 1K-1C-water rats (12 out of 18) had normal arterial pressure at sacrifice. In these normotensive 2K-salt, 1K-1C-water, and 1K-DOCA-salt animals, intimal mononuclear cells (which emigrated from the blood) increased between three- and ninefold. In these same normotensive 1K-1C-water and 1K-DOCA-salt rats, endothelial cell mitoses increased three- to sixfold with a corresponding increase in endothelial cell numbers. In the latter two groups, there was no evidence of endothelial cell denudation or changes in aortic circumference, and the subendothelial space widened mainly with reticular basement membrane presumably synthesized by the endothelium. In normotensive 1K-DOCA-salt rats, most of the endothelial cells were thick and there were several intercellular gaps. Endothelial proliferation, synthesis of macromolecules, and gap formation, as well as increased mononuclear cell emigration, indicate functional changes in mononuclear cells and in endothelial cells. We suggest that the experimental procedures designed to produce hypertension also generate factor(s) which activates mononuclear cells and/or endothelial cells. This cellular activation leads to intimal changes independent of hypertension.

Animals↗
PubMed1987

Altered adrenergic control in hypercholesterolemia.

Vascular reactivity is altered by hypercholesterolemia and atherosclerosis. Animal studies have shown that serotonergic mechanisms of vasoconstriction are enhanced, while the changes with adrenergic mechanisms are still equivocal. Serum lipids are increased with beta-blocker and diuretic therapy for hypertension. Thus, the increase in serum lipids may be responsible for both structural and functional abnormalities of the vascular system in hypertensive patients. In contrast, recent reports have suggested that alpha 1-adrenergic receptor inhibition, useful in hypertension therapy, may exert a beneficial effect on plasma lipids. We have also collected preliminary data in our laboratory examining the effects of alpha 1-adrenergic receptor inhibition with prazosin on plasma cholesterol levels and vascular reactivity in monkeys with hypercholesterolemia. We observed large reductions in both total cholesterol and the very-low-density lipoprotein (VLDL) + low-density lipoprotein (LDL) fraction of cholesterol in these animals during treatment with prazosin. Thus, in addition to its sympatholytic action on the vasculature, alpha 1-adrenergic receptor inhibition appears to exert a beneficial effect in reducing total cholesterol levels.

Adrenergic alpha-Antagonists↗
PubMed1986

Cellular changes during hypertension: a quantitative study of the rat aorta.

Using rats made hypertensive by aortic ligation or by the one kidney--one clip method, we searched the aorta for morphologic clues that could explain why hypertension aggravates atherosclerosis. Both atherosclerosis and hypertension are characterized by an increased migration of mononuclear cells into the aortic intima; we therefore quantitated this phenomenon and studied its time course. In the thoracic aorta of hypertensive rats intimal cells (emigrated mononuclear cells) increased up to 15 times 2 weeks after surgery and remained stationary thereafter. In both control and experimental rats, leukocyte emigration was heavier in the thoracic aorta than in the abdominal region. A two- to threefold increase in medial smooth muscle herniae into the intima (myointimal herniae) was also found at 8 weeks, indicating a smooth muscle cell dysfunction. Electron microscopic study of the intima showed that its thickening was due to blood-borne material and also to extracellular matrix synthesized by the endothelium. Heightened secretion reflects cell activation, a condition that (in the endothelium) leads also to leukocyte adhesion. These data suggest that, in renovascular hypertension, the aortic endothelium is in an activated state, possibly through a hormonal stimulus.

Animals↗
PubMed1986

The popliteal lymph node of the mouse: internal architecture, vascular distribution and lymphatic supply.

The architecture of the mouse popliteal lymph nodes differs from that shown in conventional diagrams. The cortical lymphoid tissue, rather than forming a continuous outer layer, is organised into one or two hemispherical aggregates which project towards the hilus. These aggregates are surrounded by medullary tissue which thus extends to large areas of the surface of the node. The vascular distribution in the lymphoid aggregates is relatively sparse and contrasts with the dense meshwork of capillaries and venules around them. It also contrasts with the high vascularity of medullary tissue. Arterial vessels, especially those of larger calibre, are predominantly seen in the hilar area of the node suggesting that there is extensive branching as the artery enters the node. Capillaries associated with the lymphoid aggregates are usually lined by continuous endothelium, while those in the medulla are generally of the fenestrated type. The microcirculation has an extensive venous capacity and many venous segments are high endothelium venules whose walls are permeated by lymphocytes. Each node receives one or two afferent lymphatic vessels and is drained by up to four or five efferent lymphatic vessels. In approximately half the nodes examined, there were extranodal communications between afferent and efferent lymphatic vessels allowing some lymph to bypass the node.

Animals↗
PubMedDate not supplied

Effect of dietary fat saturation and cholesterol on LDL composition and metabolism. In vivo studies of receptor and nonreceptor-mediated catabolism of LDL in cebus monkeys.

The mechanism(s) by which polyunsaturated fats reduce low density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B were investigated in 20 cebus monkeys (Cebus albifrons) fed diets containing corn oil or coconut oil as fat (31% of calories) with or without dietary cholesterol (0.1% by weight) for 3 to 10 years. Coconut-oil feeding compared to corn-oil feeding resulted in significant increases in levels of plasma total cholesterol (176%), very low density lipoprotein (VLDL)-LDL cholesterol (236%), high density lipoprotein (HDL) cholesterol (148%), apo B (78%), and apo A-I (112%). The addition of dietary cholesterol to corn oil compared to corn oil alone resulted in smaller, but significant, increases in levels of total cholesterol (44%), HDL cholesterol (40%), and apo A-I (33%). Although the increases in VLDL-LDL cholesterol were of similar magnitude (52%), they barely failed to reach statistical significance (p less than 0.08), while the changes in apo B levels were negligible. The addition of dietary cholesterol to coconut oil, compared to coconut oil alone, resulted in no significant changes in lipoprotein cholesterol or apoproteins, although levels of VLDL-LDL cholesterol and apo B values increased 22% and 16%, respectively. Although hepatic free cholesterol content was not altered by diet, coconut-oil compared to corn-oil feeding resulted in significant increases in hepatic cholesteryl esters (236%) and triglycerides (325%), the latter increasing still further when dietary cholesterol was added to coconut oil (563%). To further assess the effects of these dietary changes on LDL metabolism, radioiodinated normal and glucosylated LDL kinetics were performed. The production rate of LDL apo B was not altered by diet. With corn-oil feeding, 63% of LDL catabolism was via the receptor-mediated pathway. Coconut-oil compared to corn-oil feeding resulted in a 50% decrease in receptor-mediated LDL apo B fractional catabolic rate (FCR) and a 27% reduction in nonreceptor-mediated LDL apo B FCR. The addition of dietary cholesterol to corn oil, compared to corn oil alone, resulted in no significant effect on LDL apo B catabolism. The addition of dietary cholesterol to coconut oil, compared to coconut oil alone, was associated with no significant change in nonreceptor catabolism of LDL apo B but with a 58% decrease in receptor-mediated catabolism of LDL (p less than 0.059). The diet-induced alterations of LDL catabolism were significantly correlated with hepatic lipids, which were enriched in saturated fatty acids.(ABSTRACT TRUNCATED AT 400 WORDS)

Adipose Tissue↗