Cardiovascular & Hematological Disorders - Drug Targets

ISSN: 1871-529X

Current Drug Targets - Cardiovascular & Hematological Disorders
Volume 6, Number 3, September 2006

Contents


Assessment of Selective Homing and Contribution to Vessel Formation of Cryopreserved Peripherally Injected Bone Marrow Mononuclear Cells Following Experimental Myocardial Damage Pp. 141-149
M.M. Ciulla, S. Ferrero, E. Montelatici, U. Gianelli, P. Braidotti, S. Calderoni, R. Paliotti, G. Annoni, E. De Camilli, G. Busca, F. Magrini, S. Bosari, L. Lazzari and P. Rebulla
[Abstract]


Nutritional Control, Gene Regulation, and Transformation of Vascular Smooth Muscle Cells in Atherosclerosis Pp. 151-168
A. Linares, S. Perales, R.J. Palomino-Morales, M. Castillo and M.J. Alejandre
[Abstract]


Physiological and Pharmacological Insights into the Role of Ionic Channels in Cardiac Pacemaker Activity Pp. 169-190
B. Couette, L. Marger, J. Nargeot and M. E. Mangoni
[Abstract]


Development of Monoclonal Antibodies that Inhibit Platelet Adhesion or Aggregation as Potential Anti-Thrombotic Drugs Pp. 191-209
S.F. De Meyer, K. Vanhoorelbeke, H. Ulrichts, S. Staelens, H.B. Feys, I. Salles, A. Fontayne and H. Deckmyn
[Abstract]


Novel Agents to Manage Dyslipidemias and Impact Atherosclerosis Pp. 209-217
S. Nachimuthu and P. Raggi
[Abstract]


Vasculogenesis of the Embryonic Heart: Contribution of Nucleated Red Blood Cells to Early Vascular Structures Pp. 219-225
A. Ratajska and E. Czarnowska
[Abstract]




Abstracts

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Assessment of Selective Homing and Contribution to Vessel Formation of Cryopreserved Peripherally Injected Bone Marrow Mononuclear Cells Following Experimental Myocardial Damage
M.M. Ciulla, S. Ferrero, E. Montelatici, U. Gianelli, P. Braidotti, S. Calderoni, R. Paliotti, G. Annoni, E. De Camilli, G. Busca, F. Magrini, S. Bosari, L. Lazzari and P. Rebulla

In view of a potential clinical use we aimed this study to assess the selective homing to the injured myocardium and the definitive fate of peripherally injected labeled and previously cryopreserved Bone Marrow Mononuclear cells (BMMNCs).

The myocardial damage (cryoinjury) was produced in 59 rats (45 treated, 14 controls). From 51 donor rats 4.4 x 10⁹ BMMNCs were isolated and cryopreserved (slow-cooling protocols); the number of CD34+ and the viability of pooled cells was assessed by flow-cytometry analysis before and after cryopreservation and simulated delivery through a 23G needle. Seven days after injury, BMMNCs were thawed, labeled with PKH26 dye and peripherally injected (20 x 10⁶ cells in 500 μl) in recipient rats. Two weeks after experimental injury, the heart, lungs, liver, kidneys, spleen and thymus were harvested to track transplanted cells. Except a small amount in the spleen, PKH26+ cells were found only in the infarcted myocardium of the treated animals. Typical vascular structures CD34+ were found in the infarcted areas of all animals; treated rats showed a significantly higher number of these structures if compared with untreated. Morphological ultra-structural examination of infarcted areas confirmed in treated rats the presence of early-stage PKH26+ vascular structures derived from injected BMMNCs. The estimated mean CD34+ cells loss due to the cryopreservation procedure and to the system of delivery was 0.24% and 0.1%, respectively, confirming the feasibility of the procedure.

This study supports the possible therapeutic use of cryopreserved peripherally injecetd BMMNCs as a source of CD34+ independent vascular structures following myocardial damage.


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Nutritional Control, Gene Regulation, and Transformation of Vascular Smooth Muscle Cells in Atherosclerosis
A. Linares, S. Perales, R.J. Palomino-Morales, M. Castillo and M.J. Alejandre

Contractile-state smooth muscle cells (SMC), the only cell type in the arterial media, undergoes migration to the intima, proliferation, and abundant extracellular matrix production during the early stages of atherosclerosis. This involves the ingestion of low-density lipoprotein (LDL) and modified or oxidised LDL by macrophages together with SMC by several pathways including a scavenger pathway leading to accumulation of cholesterol esters and formation of foam cells. High-plasma cholesterol levels constitute a major causative risk for atherosclerosis. The membrane-bound transcription factor called sterol regulatory element binding protein (SREBP) activates gene-encoding enzymes of cholesterol and fatty acid biosynthesis. The SREBP expression, in response to diet, shows that are involved in both lipogenesis and cholesterol homeostasis, moreover SREBPs are regulated directly by cholesterol. Animal models were used in trials of athero-sclerosis, and cholesterol feeding has been described elsewhere as producing atherosclerotic lesions. We have examined the morphological, molecular and proliferative change in arterial SMC mimicking such a cholesterol diet, this transformed SMC is a good model to study the alterations of the differentiated state of SMC, and the transformation into foam cell, caused by cholesterol-rich diet. Despite the complexity of the interactions in atherosclerosis, there are many opportunities to affect the homeostatic balance of the artery wall at SMC levels. We have considered here some of the possible targets for intervention with promising strategies for the nutritional control of the genes, and, in a general way, the possibilities for modulating the expression of genes influencing atherosclerosis.


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Physiological and Pharmacological Insights into the Role of Ionic Channels in Cardiac Pacemaker Activity
B. Couette, L. Marger, J. Nargeot and M. E. Mangoni

The generation of cardiac pacemaker activity is a complex phenomenon which requires the coordinated activity of different membrane ionic channels, as well as intracellular signalling factors including Ca²⁺ and second messengers. The precise mechanism initiating automaticity in primary pacemaker cells is still matter of debate and certain aspects of how channels cooperate in the regulation of pacemaking by the autonomic nervous system have not been entirely elucidated. Research in the physiopathology of cardiac automaticity has also gained a considerable interest in the domain of cardiovascular pharmacology, since accumulating clinical and epidemiological evidence indicate a link between an increase in heart rate and the risk of cardiac mortality and morbidity. Lowering the heart rate by specific bradycardic agents in patients with heart disease constitutes a promising way to increase cardioprotection and improve survival. Thus, the elucidation of the mechanisms underlying the generation of pacemaker activity is necessary for the development of new therapeutic molecules for controlling the heart rate. Recent work on genetically modified mouse models provided new and intriguing evidence linking the activity of ionic channels genes to the generation and regulation of pacemaking. Importantly, results obtained on genetically engineered mouse strains have demonstrated that some channels are specifically involved in the generation of cardiac automaticity and conduction, but have no functional impact on the contractile activity of the heart. In this article, we will outline the current knowledge on the role of ionic channels in cardiac pacemaker activity and suggest new potential pharmacological targets for controlling the heart rate without concomitant negative inotropism.


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Development of Monoclonal Antibodies that Inhibit Platelet Adhesion or Aggregation as Potential Anti-Thrombotic Drugs
S.F. De Meyer, K. Vanhoorelbeke, H. Ulrichts, S. Staelens, H.B. Feys, I. Salles, A. Fontayne and H. Deckmyn

Cardiovascular disease is the major cause of mortality in Western countries. Platelets play a crucial role in the development of arterial thrombosis and other pathophysiologies leading to clinical ischemic events. In the damaged vessel wall, platelets adhere to the subendothelium through an interaction with von Willebrand factor (VWF), which forms a bridge between subendothelial collagen and the platelet receptor glycoprotein (GP) Ib/IX/V. This reversible adhesion allows platelets to roll over the damaged area, decreasing their velocity and resulting in strong platelet activation. This leads to the conformational activation of the platelet GPIIb/IIIa receptor, fibrinogen binding and finally to platelet aggregation. As each interaction (collagen–VWF, VWF–GPIb and GPIIb/IIIa–fibrinogen) plays an essential role in primary haemostasis, loss of either of these interactions results in a bleeding diathesis, implying that interfering with these interactions might result in an anti-thrombotic effect. Whereas GPIIb/IIIa antagonists indeed are effective anti-thrombotics, it has been suggested that drugs which block the initial steps of thrombus formation (collagen–VWF or VWF–GPIb interaction) might have advantages over the ones that merely inhibit platelet aggregation. In this review we will discuss and compare the development of monoclonal antibodies (moAbs) that inhibit platelet adhesion or platelet aggregation. The effect of the moAbs in in vitro experiments, in in vivo models and in clinical trials will be described. Benefits, limitations, current applications and the future perspectives in the development of antibodies for each target will be discussed.


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Novel Agents to Manage Dyslipidemias and Impact Atherosclerosis
S. Nachimuthu and P. Raggi

Strong epidemiological evidence linked elevated levels of low-density lipoprotein cholesterol (LDL-C) to risk of atherosclerotic heart disease. As a consequence, LDL-C lowering has been the main goal of therapy to reduce cardiovascular risk for the past few decades and hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have become some of the most commonly prescribed drugs. In spite of the proven efficacy of these drugs, statins reduce cardiovascular events by only 30-40%. Epidemiological analyses clearly indicate that a significant portion of risk is linked to other particles such as low high-density lipoprotein cholesterol (HDL-C), high triglycerides and others. Furthermore, several quantitative coronary angiography studies showing regression of atherosclerosis and reduction in subsequent events utilized a combination of drugs effective on LDL-C as well as other lipoproteins. Hence, several new drugs are be-ing investigated that affect more than the traditional LDL-C pathways. In this article, we review lipoprotein-modifying agents that have either been recently released, or are still in various phases of development. They include agents that reduce LDL-C levels by mechanisms other than HMG-CoA inhibition (such as cholesterol absorption inhibitors, Acyl-CoA cholesterol acyl transferase inhibitors, sterol-regulating binding protein cleavage activating protein ligands, microsomal triglyceride transfer protein inhibitors, LDL-C receptor activators and farnesoid X receptor antagonists) and agents that raise HDL-C cholesterol or improve cholesterol efflux (such as cholesterol ester transfer protein inhibitors, retinoid X receptor selective agonists, specific peroxisome proliferator-activated receptor (PPAR) agonists and estrogen like compounds).


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Vasculogenesis of the Embryonic Heart: Contribution of Nucleated Red Blood Cells to Early Vascular Structures
A. Ratajska and E. Czarnowska

During embryogenesis, coronary vessels develop via vasculogenesis and angiogenesis. Vasculogenesis is formation in situ of primary vessels from angioblasts - endothelial cell progenitors, and angiogenesis is formation of vessels from the existing ones. In the embryonic heart vasculogenesis precedes and overlaps angiogenesis and lasts till the end of the fetal life. What is unique about heart vasculogenesis is the fact that nucleated blood cells accompany early angioblasts in a spatiotemporal way. Morphologically these structures resemble yolk sac blood islands, thus, they have been called blood-island-like structures. In addition, these early vascular structures (blood-island-like) are found in the heart before coronary vessel system connects with the systemic circulation. We present the recent data regarding endothelial cell properties and derivation during coronary vessel formation and hypotheses concerning a source of blood cells in early vascular structures of the heart; the latter has received little attention in the literature. This review summarizes current knowledge on the endothelial cell origination from epicardial mesothelium or liver primordium. This review also focuses on blood cell contribution to coronary vessel vasculogenesis. The role of proepicardium in the epicardial cover formation and the epicardium as a source of cellular components of coronary vasculature and interstitial fibroblasts is presented. It seems that blood cells and angioblasts, which form the early vascular structures do not derive from the same hemangioblastic precursor.