Biomedical subjects

Boris Z Simkhovich

Publications and source records attributed to Boris Z Simkhovich.

5 recordsLinked to original sources

PubMed2003

Mechanisms of myocardial ischemic preconditioning are age related: PKC-epsilon does not play a requisite role in old rabbits.

Data obtained from adult cohorts have implicated activation/translocation of protein kinase C (PKC)-epsilon as an important cellular mediator of myocardial infarct size reduction with ischemic preconditioning (PC). Age-related alterations in cellular signaling may, however, confound the extrapolation of mechanistic insight derived from adults to the aging population, the specific subset in which cardioprotection is undoubtedly most relevant. Accordingly, our aim was to investigate the role of PKC-epsilon as a mediator of infarct size reduction with PC in old vs. adult rabbits. In protocol 1, we assessed the effect of PKC-epsilon translocation inhibitor peptide (PKC-epsilon-TIP) and the pan-PKC inhibitor chelerythrine on infarct size reduction with PC in adult and approximately 4-yr-old rabbits, a population previously shown to exhibit definitive hallmarks of cardiovascular aging. Rabbits received 5 min of PC ischemia or a matched control period followed by 30 min of coronary artery occlusion and 3 h of reperfusion, with infarct size (delineated by tetrazolium staining) serving as the primary endpoint. In protocol 2, we obtained insight (by Western immunoblotting) into the subcellular redistribution of PKC-epsilon in response to the 5-min PC stimulus in adult and old rabbits. In adults, infarct size reduction with PC was abrogated by both PKC-epsilon-TIP and chelerythrine. However, in old rabbits, 1). PC-induced cardioprotection was maintained despite inhibitor treatment and 2). brief PC ischemia was not associated with activation/translocation of PKC-epsilon. Thus the mechanisms responsible for PC are age related in the rabbit heart, with no apparent, requisite role of PKC-epsilon in aging animals.

Aging↗

PubMed2003

Brief episode of ischemia activates protective genetic program in rat heart: a gene chip study.

OBJECTIVE: Brief episodes of ischemia of 20 min or less have the potential to protect the heart. Such episodes are associated primarily with reversible ischemic injury yet they induce changes in gene expression. The purpose of the study was to determine whether activation of protective genes takes place within 4 h following a brief episode of ischemia that would mimic angina pectoris. METHODS: Three groups of rats were studied. In the control (Ctrl) group, hearts were immediately excised following anesthesia; in the sham-operated (SO) group, opened-chest rats received 4 h and 20 min of no intervention; and in the group subjected to ischemia (SI) hearts received 20 min of proximal coronary occlusion followed by 4 h of reperfusion. Hearts from the SI group were divided into nonischemic (NI) and ischemic (Isc) areas. Changes in gene expression pattern were analyzed by using Affymetrix Gene Chips. RESULTS: Ischemia led to strong upregulation of mRNA transcripts for heat shock proteins 70, 27, 105, 86 and 40 kDa, vascular endothelial growth factor, brain-derived neurotrophic factor, plasminogen activator inhibitor-1, activating transcription factor 3, B-cell translocation gene 2, and growth arrest and DNA damage inducible 45 alpha protein compared to the NI tissue. The majority of mRNAs whose levels increased following brief ischemia were of a protective nature. CONCLUSION: Genetic reprogramming emerging during or following brief episodes of ischemia that simulate angina, can be characterized as protective in nature. Developing new therapeutic strategies aimed to promote this protective response represents a legitimate target for future research.

Animals↗

PubMed2003

Transplantation of neonatal cardiomyocytes after permanent coronary artery occlusion increases regional blood flow of infarcted myocardium.

BACKGROUND: Cellular cardiomyoplasty is a promising approach for rebuilding scar tissue after acute myocardial infarction. However, the angiogenic potential of transplanted immature cardiomyocytes and their effect on regional myocardial blood flow (RMBF) after coronary artery occlusion remain to be evaluated. METHODS AND RESULTS: Intramyocardial injection of cultured neonatal cardiomyocytes (4 x 10(6) cells/50-70 microliter) into the scar 1 week after permanent coronary occlusion in rats resulted in improved RMBF in the infarct 4 weeks after transplantation (radioactive microspheres, 0.97 +/- 0.18 ml/min/g) in comparison to medium-injected hearts (0.61 +/- 0.11 ml/min/g, P < 0.047). The macroscopic perfusion defect after in vivo staining with the blue dye 50% Uniperse blue was significantly smaller in the cell transplantation group (1.5 +/- 0.3% of the heart) compared to the medium group (3.0 +/- 0.6%, P < 0.017). Clusters of engrafted cells within the scar demonstrated a high capillary density (1217 +/- 114 perfused (blue) capillaries/mm(2)); however, in the scar tissue itself capillary density in the cell group (156 +/- 62/mm(2)) did not significantly differ from the medium group (125 +/- 10/mm(2)), suggesting that neo-angiogenesis was confined to regions of successful engraftment (non-infarcted tissue: 1924 +/- 114 perfused capillaries/mm(2)). The transplantation group was characterized by smaller diastolic and systolic left ventricular volumes, as assessed by intravenous ventriculography, along with thickened infarcts (0.93 +/- 0.07 vs. 0.75 +/- 0.04 mm, P < 0.020) and lower infarct expansion indices (0.64 +/- 0.07 vs. 0.83 +/- 0.06, P < 0.023), as determined by post-mortem morphometry of histologic slides. CONCLUSIONS: Transplantation of neonatal cardiomyocytes induced neo-angiogenesis in zones of successful cell engraftment within the scar, which effectively enhanced tissue perfusion.

Animals↗

PubMedDate not supplied

Gene expression profiling--a new approach in the study of myocardial ischemia.

Current technologies make it possible to study thousands of genes simultaneously in the same biological sample - an approach termed gene expression profiling. Several techniques, including (i) differential display, (ii) serial analysis of gene expression (SAGE), (iii) subtractive hybridization and (iv) gene microarrays (Gene Chips), have been developed. Recently, gene profiling was applied in studying the mechanisms of ischemic injury and ischemic preconditioning. In the case of reversible ischemia caused by one or several brief transient episodes of complete coronary occlusion (as with ischemic preconditioning), or with a more prolonged but partial coronary ligation, many up-regulated genes were related to the "cell survival program". Protective genes included mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK 3), heat shock proteins 70, 27, 22, B-crystalline, vascular endothelial growth factor, inducible nitric oxide synthase and plasminogen activator inhibitors 1 and 2. With permanent coronary occlusion lasting from 24 h to several weeks, and resulting in a true myocardial infarction (MI), the list of up-regulated genes included those related to remodeling (e.g., collagens I and III, fibronectin, laminin) and apoptosis (Bax), while many down-regulated genes were related to major energy-generating pathways in the heart, namely, fatty acid metabolism. Gene expression profiling experiments have resulted in the discovery of two different genetic programs in the heart, namely, a protective program activated upon brief episodes of transient ischemia and an injury-related one activated in response to irreversible ischemic injury. Searching for factors turning on protective genes, and turning down injury-related ones, is a justifiable approach in developing new therapeutic strategies aimed to fight ischemic heart disease.

Gene Expression↗

PubMedDate not supplied

Gene activity changes in ischemically preconditioned rabbit heart gene: discovery array study.

This study tested the hypothesis that classic ischemic preconditioning can cause changes in gene expression patterns in the rabbit heart, assessed by gene array technology. Open-chest rabbits were randomly assigned to sham-operated and ischemically preconditioned groups. The sham-operated group received 5 hours and 20 minutes of no intervention, while the ischemically preconditioned group was subjected to two episodes of preconditioning ischemia (5 minutes each) separated by 5 minutes of reperfusion, followed by an additional 5 hours and 5 minutes of reperfusion. (33)P-labeled cDNA from the sham-operated hearts and the nonischemic and preconditioned areas of the ischemically preconditioned group was hybridized to filters spotted with 18,376 human cDNA clones. Altogether, 35 genes with significantly altered expression patterns were discovered. In the preconditioned area, genes for MAPKAP kinase 3 and cathepsin G were up-regulated. In the nonischemic area, genes for GTP exchange factor, Na(+), K(+)-ATPase, Zn finger protein 35, a representative of the CEA family, cytochrome c oxidase, mitogen-responsive phosphoprotein, and Ran-binding protein were up-regulated. None of the identified genes had been previously reported to be involved in ischemic preconditioning.

Animals↗