[Calcification and atherosclerosis of the coronary arteries].

Calcification is a very common phenomenon in the coronary arteries, which is part of the atherosclerotic process, and the degree of calcification can predict clinical outcomes in patients at high risk of coronary events. Both the degree of calcification and the patterns of its distribution are of prognostic importance, but the relationship of coronary artery calcification with atherosclerotic plaque instability is extremely complex and not fully understood. This article is devoted to the study of calcification markers and their influence on the development of atherosclerotic foci.

[Detection of kidney dysfunction potential biomarkers with hypertension in the persons of 25-45 years].

AIM: To assess the significance of symmetrical dimethylarginine (SDMA), uromodulin, retinol-binding protein 4 (RSB-4), transforming growth factorb1 (TGF-b1), plasminogen activator inhibitor 1 (PAI-1) as kidney dysfunction potential biomarkers persons with hypertension in persons 2545 years old. MATERIALS AND METHODS: The study included 147 people. Hypertension was recorded with blood pressure (BP)140/90 mm Hg, renal dysfunction with GFRCKD-EPI90 ml/min/1.73 cm2. Four groups were formed: 1 individuals with hypertension and GFR90 ml/min/1.73 cm2; 2 with hypertension and GFR90 ml/min/1.73 cm2; 3 with BP140/90 mm Hg and GFR90 ml/min/1.73 cm2; 4 with BP140/90 mm Hg and GFR90 ml/min/1.73 cm2. The groups were comparable by gender, age, and number of respondents. Creatinine, SDMA, uromodulin, RSB-4, TGF-b1, PAI-1 levels were examined in all individuals in the serum. RESULTS: The maximum values of SDMA were determined in the 1st and 3rd groups (1.30 and 1.36 mol/l). In the 1st group, an association was found between SDMA and GFR (r=-0.324;p=0.048). In the 1st group, the minimum values of uromodulin were recorded, in the 4th group the maximum values (164.86 and 188.90 ng/ml; at the same timeр=0.921). The level of RSB-4 was the highest in the 1st group, the lowest in the 4th group (88.64 and 80.05 g/ml;p=0.011). The association of RSB-4 with SDMA in the 3rd group (r=0.400;p=0.017), the 4th group (r=0.403;p=0.018) was detected. The level of TGF-b1 was 1.5 times higher in the 1st group than in the 3rd (23.16 and 15.99 g/ml;p=0.026), the association of TGF-b1 with GFR in the 1st group had the opposite direction (r=-0.452;p=0.005). The study of similar indicators of PAI-1 did not reveal its relationship with renal dysfunction in hypertension. CONCLUSION: The results of the study made it possible to consider SDMA, RSB-4, TGF-b1 as potential biomarkers of renal dysfunction in hypertension in persons 2545 years old.

Polyunsaturated Fatty Acids and Their Correlations with Parameters of Oxidative/Antioxidant Potential of the Blood and Lipoprotein-Associated Phospholipase A2 in Coronary Atherosclerosis.

We studied serum content of some polyunsaturated fatty acids and their correlations with parameters of oxidative stress (FORT), antioxidant protection (FORD), lipoprotein-associated phospholipase A2 (LP-PLA2), and serum level of LPO products in male patients with coronary atherosclerosis. The mass fraction of polyunsaturated fatty acids and FORD were lower, while LP-PLA2, FORT, and concentration of LPO products were higher than in the control group (conventionally healthy men). Negative correlations of medium strength of polyunsaturated fatty acids with inflammation markers and oxidative stress were revealed, which can indicate that the decrease in polyunsaturated fatty acids content is associated with enhanced generation of free radicals, and consequently with increased risk of early atherosclerosis development.

[Changes of Content of Matrix Metalloproteinases and Their Tissue Expression in Various Types of Atherosclerotic Plaques].

AIM: to investigate diagnostically significant for atherosclerotic plaques (ASP) of various types parameters of activity of matrix metalloproteinases (MMP-3, MMP-7, MMP-9) in homogenates, as well as tissue expression of MMP-2, MMP-9 and collagen type IV. MATERIALS AND METHODS: We included in this study 54 men with coronary atherosclerosis without acute coronary syndrome who underwent coronary artery bypass surgery with endarterectomy. In the obtained samples we determined levels of MMP-3, MMP-7, and MMP-9 (by enzyme immunoassay), as well as tissue expression of antibodies to MMP-2, MMP-9 and collagen type IV. RESULTS: In unstable plaques we observed increased activity of MMP-7 and MMP-9, significant increase of tissue expression of MMP-2 and MMP-9, and decreased expression of type IV collagen. Of three types of unstable ASP the highest tissue expression of MMP-9 was found in plaques of lipid type compared with plaques of necrotic and inflammatory-erosive types. Expression of type IV collagen predominated in plaques of necrotic type. CONCLUSION: The data obtained allows us to speak about tissue expression of collagen as the marker of fibrous cap stability; the presence of metalloproteinases in necrotic detritus, collagen fibers, and cellular elements can characterize an ASP as unstable or being in the transitional structural state. The immunohistochemical method helps to detect structural elements that characterize instability in various types of ASP.

Differential nicotinic receptor expression in monkey basal ganglia: effects of nigrostriatal damage.

Our previous work showed that there were marked declines in (125)I-alpha-conotoxin MII labeled nicotinic receptors in monkey basal ganglia after nigrostriatal damage, findings that suggest alpha3/alpha6 containing nicotinic receptors sites may be of relevance to Parkinson's disease. We now investigate whether there are differential changes in the distribution pattern of nicotinic receptor subtypes in the basal ganglia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned animals compared to controls to better understand the changes occurring with nigrostriatal damage. To approach this we used (125)I-alpha-conotoxin MII, a marker for alpha3/alpha6 nicotinic receptors, and (125)I-epibatidine, a ligand that labels multiple nicotinic subtypes. The results demonstrate that there were medial to lateral gradients in nicotinic receptor distribution in control striatum, as well as ventromedial to dorsolateral gradients in the substantia nigra, which resembled those of the dopamine transporter in these same brain regions. Treatment with MPTP, a neurotoxin that selectively destroys dopaminergic nigrostriatal neurons, led to a relatively uniform decrease in nicotinic receptor sites in the striatum, but a differential effect in the substantia nigra with significantly greater declines in the ventrolateral portion. Competition analysis in the striatum showed that alpha-conotoxin MII sensitive sites were primarily affected after lesioning, whereas multiple nicotinic receptor populations were decreased in the substantia nigra. From these data we suggest that in the striatum alpha3/alpha6 nicotinic receptors are primarily localized on dopaminergic nerve terminals, while multiple nicotinic receptor subtypes are present on dopaminergic cell bodies in the substantia nigra. Thus, if activation of striatal nicotinic receptors is key in the regulation of basal ganglia function, alpha3/alpha6-directed nicotinic receptor ligands may be more relevant for Parkinson's disease therapy. However, nicotinic receptor ligands with a broader specificity may be more important if receptors in the substantia nigra play a dominant role in controlling nigrostriatal activity.

Vulnerability of 125I-alpha-conotoxin MII binding sites to nigrostriatal damage in monkey.

Parkinson's disease, a neurodegenerative movement disorder characterized by selective degeneration of nigrostriatal dopaminergic neurons, affects approximately 1% of the population over 50. Because nicotinic acetylcholine receptors (nAChRs) may represent an important therapeutic target for this disorder, we performed experiments to elucidate the subtypes altered with nigrostriatal damage in parkinsonian monkeys. For this purpose we used (125)I-alpha-conotoxin MII (CtxMII), a relatively new ligand that identifies alpha3 and/or alpha6 subunits containing nAChR subtypes. In brain from untreated monkeys, there was saturable (125)I-alpha-CtxMII binding to a single population of high-affinity nicotinic sites (K(d) = 0.9 nm), primarily localized in the visual, habenula-interpeduncular, and nigrostriatal-mesolimbic pathways. Administration of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine resulted in damage to the nigrostriatal system and parkinsonism. Autoradiographic analysis showed that (125)I-alpha-CtxMII sites were selectively reduced (>/=99%) in the basal ganglia and that the lesion-induced decreases correlated well with declines in the dopamine transporter, a marker of dopaminergic neuron integrity. These findings may indicate that most or all of (125)I-alpha-CtxMII-labeled nAChR subtypes in the basal ganglia are present on nigrostriatal dopaminergic neurons, in contrast to (125)I-epibatidine sites. These data suggest that the development of ligands directed to nAChR subtypes containing alpha3 and/or alpha6 subunits may yield a novel treatment strategy for parkinsonian patients with nigrostriatal dopaminergic degeneration.

Differential alterations in nicotinic receptor alpha6 and beta3 subunit messenger RNAs in monkey substantia nigra after nigrostriatal degeneration.

Our previous studies showed that alpha4, alpha6, alpha7, beta2, beta3 and beta4 nicotinic acetylcholine receptor messenger RNAs are present in monkey substantia nigra, with a particularly intense and localized labelling of the alpha6 and beta3 subunit messenger RNAs to this brain region. Because loss of nigrostriatal neurons is a central feature of Parkinson's disease and evidence suggests that nicotinic agonists potentiate antiparkinsonian effects of L-dopa, experiments were done to determine whether nicotinic receptor subunit messenger RNAs and binding sites were altered in the basal ganglia after nigrostriatal degeneration. Squirrel monkeys (Saimiri sciureus) were rendered parkinsonian by systemic injection of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine. Behavioral studies showed that this treatment decreased baseline motor activity to 36+/-11% of control. One month after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration, caudate and putamen dopamine levels were reduced to 51+/-15% and 43+/-6% of control, respectively, while the number of tyrosine hydroxylase-positive neurons in the substantia nigra was 75+/-6% of control. Despite the reduction in nigral cell number after nigrostriatal degeneration, there were no changes in alpha4, alpha7, beta2 and beta4 messenger RNA levels in the substantia nigra. In contrast, alpha6 mRNA levels were significantly increased (143+/-10%) and the beta3 transcript decreased (62+/-6%) in the substantia nigra after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Declines were also observed in [125I]epibatidine binding in both the caudate-putamen and substantia nigra, with no change in alpha7 receptor binding. These results may suggest a dissociation in the regulation of receptor messenger RNA and binding sites, and/or that there are differential alterations in the different receptor subtypes measured using [125I]epibatidine. The changes in the two nicotinic receptor subunit messenger RNAs, alpha6 and beta3, which exhibit a selective localization to the substantia nigra, may indicate that nicotinic receptors containing these subunits are altered after nigrostriatal degeneration.

Localization of nicotinic receptor subunit mRNAs in monkey brain by in situ hybridization.

Nicotinic receptors are implicated in memory, learning, locomotor activity, and addiction. Identification of the specific receptor subtypes that mediate these behaviors is essential for understanding their role in central nervous system (CNS) function. Although expression of nicotinic receptor transcript has been studied in rodent brain, their localization in the monkey CNS, which may be a better model for the human brain, is not yet known. We therefore investigated the distribution of alpha4, alpha6, alpha7, beta2, beta3, and beta4 receptors subunit mRNAs in the monkey brain by using in situ hybridization. alpha4 and alpha7 mRNAs were very widely expressed, with a substantial degree of overlap in their distribution, except for the reticular nucleus of the thalamus in which alpha7 mRNA was much more prominently expressed. beta2 and beta4 mRNA were also widely distributed, although beta4 was more prominently localized in thalamic nuclei than beta2. The distribution of alpha6 and beta3 mRNA was very distinct from that of the other transcripts, being restricted to catecholaminergic nuclei, the cerebellum, and a few other areas. Although there were similarities in distribution of the nicotinic receptor subunit mRNAs in monkey and rodent brain, there were prominent differences in areas such as the caudate, putamen, locus coeruleus, medial habenula, and cerebellum. In fact, the distribution of alpha4 and alpha7 mRNAs in the monkey caudate and putamen was more similar to that reported in the human than rodent brain. These findings have implications for the development of drug therapies for neurological disorders, such as Alzheimer's and Parkinson's disease, in which nicotinic receptors are decreased.