lipid-a and Coronary-Disease

Hemoglobin (Hb) uniquely associates with proinflammatory HDL in atherogenic mice and coronary heart disease (CHD) patients. In this paper, we report that Hb and its scavenger proteins, haptoglobin (Hp) and hemopexin (Hx) are significantly increased in apoA-1-containing particles of HDL both in mouse models of hyperlipidemia and in CHD patients, when compared with wild type mice and healthy donors, respectively. We further demonstrate that the association of Hb, Hp, and Hx proteins with HDL positively correlates with inflammatory properties of HDL and systemic inflammation in CHD patients. Interestingly, HDL from Hp(-/-) mice under atherogenic conditions does not accumulate Hb and is anti-inflammatory, suggesting that (i) Hp is required for the association of Hb with HDL and (ii) Hb x Hp complexes regulate the inflammatory properties of HDL. Moreover, treatment of apoE(-/-) mice with an apoA-1 mimetic peptide resulted in significant dissociation of Hb x Hp complexes from HDL and improvement of HDL inflammatory properties. Our data strongly suggest that HDL can become proinflammatory via the Hb x Hp pathway in mice and humans, and dissociation of Hb x Hp x Hx complexes from apoA-1-containing particles of HDL may be a novel target for the treatment of CHD.

Topics: Adult; Aged; Animals; Apolipoprotein A-I; Biomarkers; Coronary Disease; Female; Haptoglobins; Heme; Hemoglobins; Humans; Hyperlipidemias; Inflammation; Interleukin-10; Interleukin-6; Lipid A; Lipoproteins, HDL; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Middle Aged; Reactive Oxygen Species; Young Adult

The research included 200 subjects, of which 150 had angiographically proven coronary disease with the coronary artery stenosis of 50% or more, and 50 subjects who did not have angiographically proven coronary disease. Patients were chosen randomly out of approximately 1000 patients who underwent angiography. All the subjects were treated at the Clinical Center of University of Tuzla--at the Clinic for Cardiovascular Diseases. The average value of homocysteine concentration in plasma of patients with angiographically proven coronary disease was 13.86 micromol/L, and 10.65 micromol/L in the controls, which is statistically significant difference (P < 0.0001). Lowered values of ejective fraction of the left ventricle of 50% and over was found in 25 patients (or 16.66%) with angiographically proven coronary disease, while the control group had only 4 subjects (or 8%). Student's t-test have proven that the average values of ejective fraction of the left ventricle of subject with angiographically proven coronary disease were statistically significantly different in comparison with the values of ejective fraction of the subjects in the control group (t = 5.87, df = 197, P < 0.0001). In all the groups the negative values of coefficients of correlation (R) shows that with the increase of plasma homocysteine concentrations the ejective fractions of the left ventricle dropped. Using logistical regressive analysis it was established that the following factors contribute the most to the development of coronary disease: increased concentration of plasma LDL-cholesterol, increased concentration of plasma homocysteine, diabetes mellitus and hereditary factors. In all the different forms of angiographically proven coronary disease (coronary disease in a one-vessel or in multiple-vessels), the increased concentration of plasma homocysteine was the significant risk factor for the development of coronary disease.

Topics: Coronary Angiography; Coronary Disease; Female; Homocysteine; Humans; Lipid A; Male

Apolipoprotein(a) isoforms of low-molecular weight are associated with coronary heart disease. However, because of the high number of apolipoprotein(a) isoforms, it is difficult to assess the cardiovascular risk linked to the apolipoprotein(a) gene of a subject; indeed a cut-off of apolipoprotein(a) polymorphism has not been established. The aim of this investigation was to identify an 'operative' cut-off that discriminates apolipoprotein(a) isoforms associated with high genetic risk for coronary heart disease.. Two hundred and fifty-one patients with coronary heart disease and 284 controls were recruited. Apolipoprotein(a) isoforms were detected using a high-resolution phenotyping method.. Twenty-seven apolipoprotein(a) isoforms with apparent molecular weight varying from 280 to 820 kDa were identified. Several cut-offs of apolipoprotein(a) polymorphism were used in order to compare the frequencies of apolipoprotein(a) isoforms of low and high molecular weight between patients and controls: the cut-off between 640 and 655 kDa had the highest chi 2 (130.40). Even when possible differences in apolipoprotein(a) phenotypes (subjects with at least one isoform of low molecular weight and subjects with only isoforms of high molecular weight) were assessed, the same cut-off showed the highest chi 2 (122.47). Multivariate analysis showed that apolipoprotein (a) isoforms had the greatest predictive value for coronary heart disease (F value = 107.0720), when the cut-off between 640 and 655 kDa was used.. The cut-off between 640 and 655 kDa appears to be the most efficient in identifying subjects at high cardiovascular risk linked to apolipoprotein(a) gene, since this cut-off discriminates apolipoprotein(a) isoforms expressing a greater risk for coronary heart disease.

Topics: Aged; Apolipoproteins A; Chi-Square Distribution; Coronary Disease; Female; Genetic Predisposition to Disease; Humans; Lipid A; Male; Middle Aged; Molecular Weight; Phenotype; Polymorphism, Genetic; Prognosis; Protein Isoforms; Regression Analysis; Risk Factors; Statistics, Nonparametric

Ischemic preconditioning has been proposed to protect the heart against infarction by increasing 5'-nucleotidase (5'-NT) activities and augmenting adenosine levels during sustained coronary artery occlusion. To test this theory, anesthetized dogs received four 5-min episodes of preconditioning ischemia, pretreatment with the pharmacological "preconditioning mimetic" monophosphoryl lipid A (MLA, 35 micrograms/kg i.v.) or no intervention before coronary artery ligation. At 20 min into occlusion (the crucial time at which myocyte death begins in this model), myocardial samples were obtained for measurement (by high-performance liquid chromatography) of ectosolic and cytosolic 5'-NT activity and adenosine levels. Preconditioning and MLA pretreatment limit infarct size in the canine model by 75 and 50%, respectively. However, only MLA augmented 5'-NT activity [i.e., cytosolic 5'-NT in the ischemic subendocardium was 26 +/- 1, 39 +/- 7, and 26 +/- 6 nmol. mg protein-1. min-1 in preconditioned, MLA, and control groups (P < 0.05), respectively]. Moreover, adenosine levels (in nmol/mg protein) were increased with MLA treatment (2.30 +/- 0.44) but attenuated in preconditioned dogs (1.11 +/- 0.23; P < 0.05) versus controls (1.87 +/- 0.29). Thus 5'-NT and adenosine levels need not be increased beyond control values during sustained occlusion to elicit cardioprotection.

Topics: 5'-Nucleotidase; Adenosine; Adenosine Triphosphate; Animals; Coronary Disease; Dogs; Energy Metabolism; Ischemic Preconditioning, Myocardial; Lipid A; Myocardium; Phosphates

Topics: Adult; Aged; Aged, 80 and over; Apolipoproteins A; Coronary Angiography; Coronary Disease; Female; Humans; Linear Models; Lipid A; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Prospective Studies

The effects of a 1- or 24-hour pretreatment regimen with monophosphoryl lipid A (MLA, 35 micrograms/kg i.v.) on myocardial stunning produced by repetitive coronary occlusions were studied in barbital-anesthetized dogs. Regional segment function (%SS) and myocardial blood flow were measured by sonomicrometry and the radioactive microsphere technique, respectively. In controls, six 5-min periods of coronary occlusion interpersed with 10-min periods of reperfusion and ultimately followed by 2 h of reperfusion produced regional segment dysfunction. Pretreatment with MLA for 1 h prior to the first occlusion period had no effect on %SS, however, pretreatment with MLA 24 h prior to the first occlusion period resulted in a significant (p < 0.05) improvement in the recovery of %SS at all reperfusion periods as compared to the control group. In addition, segment dysfunction during each occlusion period was significantly less severe in animals receiving a 24-hour pretreatment with MLA as compared to the controls. These results are the first to demonstrate that MLA, a lipid A derivative of endotoxin, preserves contractile function of ischemic myocardium in an in vivo canine model and that its cardio-protection is time dependent.

Topics: Animals; Arterial Occlusive Diseases; Blood Gas Analysis; Body Weight; Coronary Circulation; Coronary Disease; Dogs; Female; Hemodynamics; Hydrogen-Ion Concentration; Hypertrophy, Left Ventricular; Lipid A; Male; Microspheres; Myocardial Contraction; Myocardial Reperfusion Injury; Organ Size