John W. Gaubatz
Baylor College of Medicine
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Arteriosclerosis, Thrombosis, and Vascular Biology | 1989
G. L. Cushing; John W. Gaubatz; M. L. Nava; B. J. Burdick; T M Bocan; John R. Guyton; D. Weilbaecher; Michael E. DeBakey; Gerald M. Lawrie; Joel D. Morrisett
Lp[a] is a lipoprotein whose plasma concentration is highly correlated with cardiovascular disease. Its protein moiety, apoLp[a], consists of two large polypeptides, apo[a] and apo B. The possible contribution of Lp[a] to atherosclerosis in saphenous vein aortocoronary bypass grafts was studied in a population of patients undergoing coronary re-bypass surgery. The vein graft tissue levels of apoLp[a] were compared with graft duration, gross and light microscopic pathology, as well as plasma levels of apoLp[a]. The localization pattern of apo[a] and apo B in vein graft tissue was determined. In addition, the plasma levels of cholesterol, triglycerides, apoproteins (apo) A-I, A-II, and E were measured. In a representative subpopulation of 17 patients with a mean age of 63 years from whom grafts with a mean duration of 112 months were resected, the mean total plasma cholesterol level was 221 mg/dl, the mean high density lipoprotein cholesterol level was 31 mg/dl, and the mean plasma triglyceride level was 228 mg/dl. In normal saphenous veins, the level of apoLp[a] was below measurable limits (less than 2 ng/mg), and the level of apo B was very low (3.3 ng/mg). In resected grafts, the mean tissue level of apoLp[a] was 32 ng/mg, and that of apo B was 70 ng/mg, demonstrating the net accumulation of these apoproteins in veins from the time of their grafting into the arterial bed. The apoLp[a]/apo B ratio was determined in 77 tissue segments from 59 grafts (28 patients) and was found to be 0.313. This tissue ratio was significantly higher (p = 0.02) than the plasma apoLp[a]/apo B ratio from these patients, which was 0.132. Immunostaining showed co-localization of apo[a] and apo B in the neointima of grafts. The most abundant pathologic features observed in resected grafts were proliferated intima (43/52), thrombus (28/52), and atherosclerotic core regions (21/52). The level of tissue apo B correlated well with the abundance of core regions (r = 0.501), whereas the level of tissue apoLp[a] did not correlate as well with this feature (r = 0.233). Although apo[a] and apo B are almost absent from normal saphenous vein, these apoproteins (and presumably the lipoproteins Lp[a] and low density lipoprotein) accumulate in bypass vein grafts. The data support the view that these lipoproteins play a significant role in vein graft atherosclerosis.
Circulation Research | 2006
Dan Liao; Hongmei Tan; Rutai Hui; Zhaohui Li; Xiaohua Jiang; John W. Gaubatz; Fan Yang; William Durante; Lawrence Chan; Andrew I. Schafer; Henry J. Pownall; Xiaofeng Yang; Hong Wang
We previously reported that hyperhomocysteinemia (HHcy), an independent risk factor of coronary artery disease (CAD), is associated with increased atherosclerosis and decreased plasma high-density lipoprotein cholesterol (HDL-C) in cystathionine &bgr;-synthase–/apolipoprotein E–deficient (CBS−/−/apoE−/−) mice. We observed that plasma homocysteine (Hcy) concentrations are negatively correlated with HDL-C and apolipoprotein A1 (apoA-I) in patients with CAD. We found the loss of large HDL particles, increased HDL-free cholesterol, and decreased HDL protein in CBS−/−/apoE−/− mice, and attenuated cholesterol efflux from cholesterol-loaded macrophages to plasma in CBS−/−/apoE−/− mice. ApoA-I protein was reduced in the plasma and liver, but hepatic apoA-I mRNA was unchanged in CBS−/−/apoE−/− mice. Moreover, Hcy (0.5 to 2 mmol/L) reduced the levels of apoA-I protein but not mRNA and inhibited apoA-1 protein synthesis in mouse primary hepatocytes. Further, plasma lecithin:cholesterol acyltransferase (LCAT) substrate reactivity was decreased, LCAT specific activity increased, and plasma LCAT protein levels unchanged in apoE−/−/CBS−/− mice. Finally, the clearance of plasma HDL cholesteryl ester, but not HDL protein, was faster in CBS−/−/apoE−/− mice, correlated with increased scavenger receptor B1, and unchanged ATP-binding cassette transporter A1 protein expression in the liver. These findings indicate that HHcy inhibits reverse cholesterol transport by reducing circulating HDL via inhibiting apoA-I protein synthesis and enhancing HDL-C clearance.
Atherosclerosis | 1982
Henry F. Hoff; John W. Gaubatz
Abstract LDL-like lipoproteins were extracted from a buffer-soluble fraction of homogenates of both grossly normal intima and fatty-fibrous plaques from the human aorta. A low-speed supernate of such homogenates was subjected to differential ultracentrifugation to isolate a d 1.006–1.063 density fraction which was further purified by gel filtration on agarose columns, or by affinity chromatography of low-speed supernatants of aortic homogenates on immunoabsorbents (anti-apo B). All recovered immunoreactivity for apo B as measured by electroimmunoassay was found in the retarded fraction following gel filtration or affinity chromatography. Characterization of the aorta-extracted lipoprotein containing apo B illustrated that the lipoprotein was quite similar to plasma LDL with respect to lipid composition, lipid/protein ratio, identification of apo B by polyacrylamide gel electrophoresis, and particle size by electron microscopy. However, aorta-derived lipoproteins differed from plasma LDL with respect to fatty acid composition and electrophoretic mobility. They showed an increase in stearate content which was most prominent in the cholesteryl ester and triglyceride fractions, as well as an increase in oleate and a reduction in linoleate content in both cholesteryl ester and phospholipid fractions. During purification aorta-derived lipoproteins maintained an increase in electrophoretic mobility compared to plasma LDL. This increase in surface charge might be a result of the demonstrated contamination with sulfated glycosaminoglycans (1.5% by weight). However, digestion with chondroitinase ABC had no effect on electrophoretic mobility. The lipoproteins extracted and purified from grossly normal intima and fatty-fibrous plaques possessed the same similarities as well as differences in characteristics relative to plasma LDL. The results from this study suggest that the lipoproteins extracted from the human aorta may represent either the preferential retention of a subclass of plasma LDL with slightly different characteristics from the average but with greater affinity for intimal material, or the products of modification of normal plasma LDL following retention by extracellular components of the aortic intima. This modification may be due to complex formation of LDL with such components.
Arteriosclerosis, Thrombosis, and Vascular Biology | 2014
Ron C. Hoogeveen; John W. Gaubatz; Wensheng Sun; Rhiannon Dodge; Jacy R. Crosby; Jennifer Jiang; David Couper; Salim S. Virani; Sekar Kathiresan; Eric Boerwinkle; Christie M. Ballantyne
Objective—To investigate the relationship between plasma levels of small dense low-density lipoprotein-cholesterol (sdLDL-C) and risk for incident coronary heart disease (CHD) in a prospective study among Atherosclerosis Risk in Communities (ARIC) study participants. Approach and Results—Plasma sdLDL-C was measured in 11 419 men and women of the biracial ARIC study using a newly developed homogeneous assay. A proportional hazards model was used to examine the relationship among sdLDL-C, vascular risk factors, and risk for CHD events (n=1158) for a period of ≈11 years. Plasma sdLDL-C levels were strongly correlated with an atherogenic lipid profile and were higher in patients with diabetes mellitus than non–diabetes mellitus (49.6 versus 42.3 mg/dL; P<0.0001). In a model that included established risk factors, sdLDL-C was associated with incident CHD with a hazard ratio of 1.51 (95% confidence interval, 1.21–1.88) for the highest versus the lowest quartile, respectively. Even in individuals considered to be at low cardiovascular risk based on their LDL-C levels, sdLDL-C predicted risk for incident CHD (hazard ratio, 1.61; 95% confidence interval, 1.04–2.49). Genome-wide association analyses identified genetic variants in 8 loci associated with sdLDL-C levels. These loci were in or close to genes previously associated with risk for CHD. We discovered 1 novel locus, PCSK7, for which genetic variation was significantly associated with sdLDL-C and other lipid factors. Conclusions—sdLDL-C was associated with incident CHD in ARIC study participants. The novel association of genetic variants in PCSK7 with sdLDL-C and other lipid traits may provide new insights into the role of this gene in lipid metabolism.
Arteriosclerosis, Thrombosis, and Vascular Biology | 2014
Ron C. Hoogeveen; John W. Gaubatz; Wensheng Sun; Rhiannon Dodge; Jacy R. Crosby; Jennifer Jiang; David Couper; Salim S. Virani; Sekar Kathiresan; Eric Boerwinkle; Christie M. Ballantyne
Objective—To investigate the relationship between plasma levels of small dense low-density lipoprotein-cholesterol (sdLDL-C) and risk for incident coronary heart disease (CHD) in a prospective study among Atherosclerosis Risk in Communities (ARIC) study participants. Approach and Results—Plasma sdLDL-C was measured in 11 419 men and women of the biracial ARIC study using a newly developed homogeneous assay. A proportional hazards model was used to examine the relationship among sdLDL-C, vascular risk factors, and risk for CHD events (n=1158) for a period of ≈11 years. Plasma sdLDL-C levels were strongly correlated with an atherogenic lipid profile and were higher in patients with diabetes mellitus than non–diabetes mellitus (49.6 versus 42.3 mg/dL; P<0.0001). In a model that included established risk factors, sdLDL-C was associated with incident CHD with a hazard ratio of 1.51 (95% confidence interval, 1.21–1.88) for the highest versus the lowest quartile, respectively. Even in individuals considered to be at low cardiovascular risk based on their LDL-C levels, sdLDL-C predicted risk for incident CHD (hazard ratio, 1.61; 95% confidence interval, 1.04–2.49). Genome-wide association analyses identified genetic variants in 8 loci associated with sdLDL-C levels. These loci were in or close to genes previously associated with risk for CHD. We discovered 1 novel locus, PCSK7, for which genetic variation was significantly associated with sdLDL-C and other lipid factors. Conclusions—sdLDL-C was associated with incident CHD in ARIC study participants. The novel association of genetic variants in PCSK7 with sdLDL-C and other lipid traits may provide new insights into the role of this gene in lipid metabolism.
Biochimica et Biophysica Acta | 1979
Henry F. Hoff; William A. Bradley; Carol L. Heideman; John W. Gaubatz; Michael Karagas; Antonio M. Gotto
Physical and chemical criteria of lipoproteins containing apolipoprotein B, extracted from human aortic intima, were compared with those of plasma low density lipoproteins (LDL). Homogenates of grossly normal intima and advanced atherosclerotic lesions were subjected to differential ultracentrifugation to isolate a d = 1.006--1.063 g/ml density fraction which was extensively characterized. By electroimmunoassay, over 90% of the recovered apolipoprotein B immunological reactivity was found in isolates from both plaques and normal intima. In isolates of plaque and normal intima, particles of the same size as LDL were found, although a small population of very large structures was also present in plaque fractions. Apolipoprotein composition was similar to that of plasma LDL except for the presence of human serum albumin in aortic isolates. Fractions from aorta demonstrated greater electrophoretic mobilities than LDL. The lipid composition of isolates from normal intima was similar to that of LDL. The lipid composition of plaque fractions showed a significant decrease in the cholesteryl ester to free cholesterol ratio and in the triglyceride content in comparison to LDL and to fractions from normal intima. The fatty acid pattern of the cholesteryl ester fraction from isolates of both normal and plaque aortic homogenates demonstrated a significant decrease in the linoleate to oleate ratio as compared to LDL. Our initial studies suggest that althought aortic fractions are similar to LDL by certain criteria, some differences observed are more pronounced in fractions from lesions than from normal intima.
Methods in Enzymology | 1986
John W. Gaubatz; Gary L. Cushing; Joel D. Morrisett
Publisher Summary This chapter discusses quantitation, isolation, and characterization of human lipoprotein (a) (lp(a)). The chapter presents several methods for detection/identification of the apolipoprotein (a) (apo(a)) antigen directly in plasma. First major technique for the detection is agarose electrophoresis. Lp(a) is demonstrable by electrophoresis of serum in 0.5% agarose gel. The technique has been used to study alterations in electrophoretic mobility produced by various chemical treatments of Lp(a). The Lp(a)-specific antigen was first detected by Berg using the double diffusion test procedure in agarose gel as developed by Ouchterlony. This chapter also discusses the process of two-dimensional immunoelectrophoresis of Lp(a). This lipoprotein migrates with pre-β mobility, and is readily detected after electrophoresis in the second dimension into agarose containing anti-Lp(a). This chapter also discusses immunochemical quantitation of the Apo(a) antigen. Suitable donors for obtaining whole plasma for isolation of Lp(a) are individuals with high Lp(a) concentrations (>75 mg/dl). Preliminary screening is done using double diffusion tests, followed by a more quantitative measurement using electroimmunoassay.
Circulation Research | 1977
Henry F. Hoff; Carol L. Heideman; Antonio M. Gotto; John W. Gaubatz
SUMMARY Apolipoprotein B (apoB) was measured in buffer-extracted homogenates of grossly normal and atherosclerotic human aortic intima by means of an electroimmunoassay procedure. The apoB values which were expressed as μg per mg tissue dry weight, varied widely, ranging from 0.34 to 18.45 in normal intima and from 0.8 to 12.5 in fatty fibrous plaques. No consistent differences in apoB content were found between normal intimas from thoracic and abdominal aortic regions. There was a statistically significant positive correlation between the quantity of buffer-extractable apoB in normal regions and the plasma cholesterol and triglyceride concentration. Bufferextractable apoB values were significantly higher in fatty fibrous plaques than in ulcerated lesions from the same vessel. However, fatty fibrous plaque apoB values were significantly lower than those from grossly normal regions from the same aorta, although the topographical distribution of apoB was more widespread in plaques than in normal regions, as shown by immunofluorescence studies. This apparent discrepancy reflected the incomplete extraction of apoB from plaques as contrasted to normal regions. The relatively loosely bound apoB, extractable by standard buffers, may represent intact low density lipoprotein (LDL) and/or very low density lipoprotein (VLDL), while the tightly bound fraction may represent insoluble complexes of intact lipoproteins within the plaque or delipidated apoB.
Journal of Lipid Research | 2007
John W. Gaubatz; Baiba K. Gillard; John B. Massey; Ron C. Hoogeveen; Max T. Huang; Eric E. Lloyd; Joe L. Raya; Chao Yuh Yang; Henry J. Pownall
Small, dense, electronegative low density lipoprotein [LDL(−)] is increased in patients with familial hypercholesterolemia and diabetes, populations at increased risk for coronary artery disease. It is present to a lesser extent in normolipidemic subjects. The mechanistic link between small, dense LDL(−) and atherogenesis is not known. To begin to address this, we studied the composition and dynamics of small, dense LDL(−) from normolipidemic subjects. NEFA levels, which correlate with triglyceride content, are quantitatively linked to LDL electronegativity. Oxidized LDL is not specific to small, dense LDL(−) or lipoprotein [a] (i.e., abnormal lipoprotein). Apolipoprotein C-III is excluded from the most abundant LDL (i.e., that of intermediate density: 1.034 < d < 1.050 g/ml) but associated with both small and large LDL(−). In contrast, lipoprotein-associated phospholipase A2 (LpPLA2) is highly enriched only in small, dense LDL(−). The association of LpPLA2 with LDL may occur through amphipathic helical domains that are displaced from the LDL surface by contraction of the neutral lipid core.
Circulation Research | 1977
Henry F. Hoff; Carol L. Heideman; John W. Gaubatz; Antonio M. Gotto; E. E. Erickson; Richard L. Jackson
SUMMARY A quantitative electroimmunodiffusion (EID) assay was developed for apolipoprotein B (apoB), the major apoprotein of human plasma low density lipoproteins (LDL) and very low density lipoproteins (VLDL). Specificity, sensitivity (30–200 ng) and reproducibility (11%) were established. We used this system to determine the amount of buffer-soluble apoB in supernatant fractions from homogenates of the intima from grossly normal human aortas. Assays of whole tissue minces yielded only one-third of the apoB in supernatant fractions. Intimal homogenates contained 0.34–18.45 &mgr;g of apoB/mg of tissue, dry weight (mean 5.42 ± 3.95 SD). We also found that no apoB was detected in the homogenates of adjacent tunica media. Furthermore, most of the intimal apoB was found in the LDL density (d) fraction (d 1.006–1.063) after differential ultracentrifugation, while the VLDL (d < 1.006) fraction contained only negligible amounts of apoB. By electron microscopy, it was determined that the LDL density fraction contained particles 200–250 A in diameter which were similar in size to plasma LDL. These results suggest that grossly normal aortas contain significant quantities of intact LDL.