Pathological Remodeling of the Myocardium in Chronic Heart Failure: Role of PGC-1α.

Pathological remodeling of the myocardium in chronic heart failure includes the development of pathological cardiac hypertrophy, reactivation of the fetal genetic program, and disorders in cardiac energy metabolism. Coactivator-1α of receptor γ activated by peroxisome proliferator (PGC-1α), a transcription coactivator of nuclear receptors and metabolism master regulator, plays an important role in cardiac metabolism regulation. Studies on the animals models of chronic heart failure have demonstrated the development of pathological cardiac hypertrophy, metabolic disorders, and reactivation of the fetal genetic program; these processes are mutually related. An important role in regulation of these processes belongs to PGC-1α; its low expression indicates low activity and down-regulation of this coactivator. Pathological cardiac hypertrophy, decrease of PGC-1α activity, and reactivation of the fetal genetic program in chronic heart failure are demonstrated.

Morphometric analysis of atherosclerotic plaques in human carotid arteries.

Morphometric analysis of 35 biopsy specimens from patients with stable (n=10) and unstable (n=25) atherosclerotic lesions was carried out. The structure of the plaques and their connective tissue caps was studied by various methods of histological sections staining. A new morphometric approach to quantitative evaluation of atherosclerotic lesions instability is suggested. It consists in calculation of the morphological "rigidity" coefficient, due to which the plaque is characterized more accurately. The proportion of areas of the "rigid" (connective tissue and calcium salt deposition areas) to "soft" (atheronecrotic nuclei, microvessels, clots and hemorrhages) structures of the plaque is evaluated. Plaque instability (liability of a to rupture) is associated with changes in the extracellular matrix components in the cap: accumulation of collagen and reduction of elastic fiber content reducing vessel elasticity and making its locally more rigid.

[Comparative transcriptome analysis of human aorta atherosclerotic lesions and peripheral blood leukocytes from essential hypertension patients].

One of the major cardiovascular risk factor which predisposes to and accelerates atherosclerosis is arterial hypertension (AH). To determine the molecular basis of the crosslink between AH and atherosclerosis for the development of new treatment strategies large-scale transcriptome analysis of the cells implicated in atherogenesis is needed. We used cDNA microarray technique for simultaneous analysis of gene expression in human abdominal aorta normal sites and atherosclerotic lesions of different histological types, as well as in peripheral blood leukocytes from patients with essential hypertension (EH) and donors. The microarray data were verified by quantitative RT-PCR (reverse transcription coupled with polymerase chain reaction) and immunohistochemical analysis. Differential expression of 40 genes has been found, among which twenty two genes demonstrated up-regulation and 18 genes demonstrated down-regulation in atherosclerotic aorta compared with normal vessel. New gene-candidates, implicated in atherogenesis, have been identified - FPRL2, CD37, CD53, RGS1, LCP1, SPI1, CTSA, EPAS1, FHL1, GEM, RHOB, SPARCL1, ITGA8, PLN, and COL14A1. These genes participate in cell migration and adhesion, phenotypic changes of smooth muscle cells, immune and inflammatory reactions, oxidative processes and extracellular matrix remodeling. We have found increased expression levels of CD53, SPI1, FPRL2, SPP1, CTSD, ACP5, LCP1, CTSA and LIPA genes in peripheral blood leukocytes from EH patients and in atherosclerotic lesions of human aorta. The majority of these genes significantly (p<0.005) positively (r>0.5) correlated with AH stage as well as with histological grading of atherosclerotic lesions.

Two types of projection neurons in human striatum: peculiarities of their somatodendritic structure in ventral and dorsal striatum.

The somatodendritic structure of projection neurons was morphometrically examined in the nucleus accumbens of human brain. In contrast to reticular neurons, spiny neurons of the nucleus accumbens and dorsal striatum have different somatodendritic structure. In both parts of the striatum, reticular neurons were NADPH-diaphorase-positive.

[The role of mast cell population in aortic intima in development of human atherosclerosis]. / Izuchenie roli populiatsii tuchnykh kletok intimy aorty v razvitii ateroskleroza u cheloveka.

AIM: To assess the role of mast cells in development of human atherosclerosis. MATERIAL: Autopsy material (transverse cross-sections of the aorta and membranous preparations of intima) from 53 persons who died of accidental causes. Original method of the study of aortic cellular populations on membranous preparations of intima allowed to analyze character of accumulation of lipids in fatty streaks, as well as changes of mast cells and relative amount of various cellular populations in intact intima and during development of early atherosclerotic lesions. RESULTS: In intact intima mast cells are consistently found, their quantity depends on age and degree of intimal hyperplasia. Density of mast cell population in age groups 17-29 and 30-49 years was 5.8 and 9.6 cells/mm2, respectively. Ratio of mast cells to total amount of lymphocytes and monocytes was 1:6. Two types of fatty streaks ('early' and 'transitional') can be distinguished depending on structure of lipid inclusions and cellular composition. Compared with intact intima 'early' fatty streaks have increased content of lymphocytes and monocytes. Average density of mast cells in early streaks is 12.2 cells/mm2 with ratio of mast cells to total amount of lymphocytes and monocytes 1:11. Development of 'transitional' fatty streaks preceding plaque formation is characterized by signs of inflammation with multifold increase of content of lymphocytes and monocytes and ratio of amount of mast cells to that of mononuclear cells 1:20. Density of mast cells including their degranulating forms is the highest (18.1 cells/mm2) on periphery of 'transitional' fatty streaks while substantially smaller amount of mast cells (3.2 cells/mm2) can be found in central areas of these streaks. CONCLUSION: Mast cells actively participate in atherogenesis, development and progression of atherosclerotic lesions. Formation of fatty streaks in human aorta is associated with signs of immune inflammation (lymphocytic-monocytic reaction and increased amount of mast cells).

[Phenotype changes in smooth muscle cells of human coronary arteries during aging and during development of atherosclerosis]. / Izmenenie fenotipa gladkomyshechnykh kletok koronarnykh arterii cheloveka s vozrastom i pri razvitii ateroskleroza.

The ultrastructure and the expression of cytoskeletal and contractile proteins were studied in the intimal cells of human coronary arteries (CA) taken at autopsy from 38 trauma victims aged 1 to 70 years. All intimal smooth muscle cells (SMC) of the CA from 2-4-year old children contained desmin, vimentin, myosin, and actin. In the normal intima of adolescents aged 14-16 years, only did some SMC contain desmin whereas in that of adults, they had no desmin, but expressed all other proteins. For example, some atherosclerotic plaques of CA exhibited desmin-positive SMC and smooth muscle myosin-free cells. The ultrastructure of SMC of atherosclerotic plaques showed profound polymorphism. In addition to typical SMC, the plaques displayed modified cells having a developed endoplasmic reticulum and Golgi complex. The fact that the atherosclerotic plaques have cells differing in ultrastructural features and protein expression, which is specific to an earlier period of the body development suggests phenotypic changes in the cells and the latter acquiring new functions that are of great significance in the pathogenesis of atherosclerosis.

[Monocyte-macrophage infiltration in portions of atherosclerotic lesions of the human aorta]. / Monotsitarno-makrofagal'naia infil'tratsiia v uchastkakh rannikh ateroskleroticheskikh porazhenii aorty cheloveka.

Human thoracic aorta was taken from trauma victims aged from 6 to 40 years. Cell composition of the intimal layer was investigated in the lesion predisposed (LP) areas of the aorta and in the lesion resistant (LR) areas. By double immunofluorescent staining with mono and polyclonal antibodies to monocytes/macrophages (Mn/Mph) and smooth muscle cells (SMC) the presence of Mn/Mph was revealed in all aortas studied. The number of these cells was 2-6 fold higher in LP areas, compared to LR areas in all persons over 21 years of age. Scanning electron microscopy revealed Mn on the luminal surface of the vessel the number of which was frequently higher in LP areas. Mn/Mph in LP areas were heterogeneous in their structure depending on the depth of their localization in the intima. The revealed Mn/Mph infiltration in aortas of young subjects may be the earliest manifestation of the atherosclerotic lesion.

[Immunocytochemical analysis of apoprotein E distribution in human tissues]. / Immunotsitokhimicheskii analiz raspredeleniia apoproteina E v tkaniakh cheloveka.

Localization of apoprotein E (apo E) has been studied in different human tissues. For this aim the immunoperoxidase method and peroxidase-antiperoxidase complex, polyclonal and monoclonal antibodies, to apo E have been used. In every human tissue analysed apo E-containing cells have been revealed. To the latter the following cell types belong: hepatocytes and hepatic sinusoidal cells, macrophages of the spleen, lymph nodes and pulmonary tissues, glial cells and cells in all layers of the adrenals, skin keratinocytes, cells of the glomerular capsule and convoluted tubules of the kidney, spermatocytes and smooth muscle cells of the testis. Besides, apo E is revealed in endothelium of some vessels. As demonstrate the results obtained, apo E is found practically in all human tissues. A suggestion is made that besides its participation in reverse cholesterol transport, this protein performs a number of additional functions, such as regulation of local hormonal homeostasis of an organ.

[The localization of apoprotein E in the normal human aortic wall and in atherosclerosis]. / Lokalizatsiia apoproteina E v stenke aorty cheloveka v norme i pri ateroskleroze.

The authors studied the distribution of apoprotein E (apoE) in normal and atherosclerotic human aortic wall. Double immunofluorescent technique and a set of mono- and polyclonal antibodies were used in the study. Apo E was found in normal intima of every aorta taken from people over 20 years of age and in vessels of some adolescents. The protein was localized extracellularly and was noted in some portion of macrophages but not in the endothelial and smooth muscle cells of human aorta. The accumulation of apo E increased in lipid strips and was particularly high in acellular zone of the atherosclerotic plaque. This effect may be due to the retention of apo E by changed sulfated glycosaminoglycans of aortic connective tissue. The accumulation of apo E in the vessel wall may have an important role in the pathogenesis of atherosclerosis.

[Dynamics of lipid accumulation on human aortic walls in atherosclerosis]. / Dinamika nakopleniia lipidov v stenke aorty cheloveka pri ateroskleroze.

The authors studied distribution of apoprotein B (apo B) and lipids containing esterified and nonesterified cholesterol (EC and NEC) in human aortic wall, using methods of indirect immunofluorescence with antibodies of apo B, and filipin and oil red 0 staining. All the examinees over 14 exhibited visually intact and atherosclerosis-affected vascular sites of accumulated apo-B-containing lipoproteins. EC, staining oil red 0, occurred only in the lipid strip and atherosclerotic plaque. Filipin-positive NEC was found in atherosclerotic plaque only. NEC disseminated extracellularly in the form of separate spherical corpuscles and homogenously. Saline pretreatment of nonfixed cryostat sections reduced the intensity of filipin homogenous staining. Mechanisms of lipids formation in vascular tissue of humans are under discussion.