Current Drug Targets - Cardiovascular & Haematological Disorders, Volume 3, Number 1, 2003
Contents
Remodeling of the Myocardium
and Potential Targets in the Collagen Degradation and Synthesis Pathways Pp.1-30
Retinoids: Pleiotropic
Agents of Therapy for Vascular Diseases? Pp.31-57
Jeffrey W.
Streb and Joseph M. Miano
New Target Molecules in the
Drug Control of Blood Pressure and Circulation Pp.59-72
Ryuji Inoue and Yasuo Mori
RAS Blockade in Experimental
Renal Transplantation. Benefits and Limitations Pp.73-79
Annemieke Smit-van Oosten, Coen A. Stegeman and Harry van Goor
Viral and Cellular Cytokines
as Therapeutic Targets in AIDS-Related Lymphoproliferative Disorders Pp.81-96
Yoshiyasu Aoki
and Giovanna Tosato
Abstracts
[Back to top] Remodeling of the Myocardium and Potential Targets in the
Collagen Degradation and Synthesis Pathways
Remodeling of the myocardium is
the major mechanism for disability and death in prevalent cardiovascular
diseases such as hypertension, heart failure and myocardial infarction (MI). It
is a complex process that involves changes in structure, shape and topography
at the global level and changes in myocytes and non-myocytes at cellular and
subcellular levels that impact negatively on function. Although the myocytes
subserve the heart’s pump function, the predominant cell type in the heart is
the fibroblast (not the myocyte). The fibroblast’s major role is deposition of
the extracellular matrix (ECM) of which collagen is the principal component.
The cardiac extracellular collagen matrix (ECCM) maintains structural and
functional integrity, and contributes to coordinated mechanical action with
every systole during life. Excessive collagen deposition or pathological
fibrosis is an important contributor to left ventricular (
[Back to top] Retinoids: Pleiotropic
Agents of Therapy for Vascular Diseases?
Retinoids, the natural and synthetic derivatives of vitamin A, exert broad biological effects and have been used clinically to treat a variety of dermatological and neoplastic diseases. The principal mode of action of many retinoids is through the binding and activation of a family of nuclear receptors that modulate gene transcription. Recent evidence demonstrates that retinoids effectively attenuate experimental vessel wall narrowing due to atherosclerosis, post-balloon injury stenosis, and bypass graft failure. Moreover, retinoids promote a differentiated phenotype in smooth muscle cells (SMC) which, unlike other muscle types, is not fixed and is subject to considerable modulation in disease states. A growing number of in vitro studies have reported desirable effects of retinoids on cell migration, proliferation, apoptosis, matrix remodeling, fibrinolysis, coagulation, and inflammation, all of which impinge on vascular disease. Since vascular SMC and endothelial cells (EC) express most retinoid receptors, the mechanisms underlying retinoid-mediated events in these cells and the vessel wall likely relate to an altered transcriptome. In fact, there is a growing list of retinoid-response genes encoding proteins that likely mediate the actions of retinoids. Retinoid-response genes, therefore, represent promising targets of therapy for the refined treatment of vascular diseases. The purpose of this review is to summarize the emerging importance of retinoids in the control of vascular cell responses with special emphasis on potential mechanisms underlying retinoid-induced changes in the vessel wall following injury. Given the similarities in the pathogenesis of neoplasia and vascular disease, it is reasonable to consider testing the efficacy of retinoids for the treatment of human vascular disease.
[Back to top] New Target Molecules in the
Drug Control of Blood Pressure and Circulation
Ion channels play a pivotal role in blood pressure regulation. Amongst them, much attention has been directed to dihydropyridine (DHP)-sensitive (L-type) voltage-dependent Ca2+ channels (VDCCs) and iberiotoxin-sensitive Ca2+-dependent K+ channels which are distributed over the whole vascular tree and contribute to vascular tone regulation. Recent advances in vascular electrophysiology have, however, added novel and interesting molecules to this repertoire. In small mesenteric arterioles, the predominant VDCC phenotype is not L-type but DHP-insensitive, high voltage-activated VDCCs that exhibit unique properties distinguishable from those of hitherto-known VDCCs. Surprisingly, mibefradil, a well-known T-type selective blocker potently inhibits these channels, and the use of this blocker has indicated that Ca2+ entry through these channels may be one of the important determinants of peripheral vascular tone. Another new candidate likely involved in blood pressure control is the mammalian homologue of Drosophila transient receptor potential (TRP) protein, including TRPC4 and TRPC6. Experiments in genetically engineered TRPC4-deficient mice have suggested that expression of TRPC4 is indispensable for agonist-induced Ca2+ entry in endothelial cells and production of nitric oxide and vasorelaxation. TRPC6 is likely to contribute to sustained Ca2+ entry into vascular smooth muscle cells activated by stimulation of sympathetic nerves and elevation of intravascular pressure. Antisense oligonucleotide experiments have suggested that this protein is an essential component of a1-adrenoceptor activated and mechanosensitive cation channels in some vascular tissues. This review overviews what is known about the role of ionic channels in blood pressure control with main focus on the above-mentioned new molecules as promising targets for drug discovery and development.
[Back to top] RAS Blockade in Experimental
Renal Transplantation. Benefits and Limitations
Annemieke Smit-van Oosten, Coen A. Stegeman and Harry van Goor
In renal transplantation, chronic renal transplant failure (CRTF) is the principal cause of late graft loss. Both immunological and non-immunological factors play a role in the pathogenesis of CRTF. However, CRTF is unresponsive to immunosuppressive therapy. In several kidney diseases, inhibition of the renin-angiotensin system (RAS) has shown to reduce the rate of progression of renal disease more effectively than conventional antihypertensive drugs. Therefore, RAS blockade may be of benefit in the treatment of CRTF. Several short-term studies in human renal transplant recipients showed that RAS blockade had a beneficial effect on renal transplant function, blood pressure and proteinuria. Despite these benefits physicians remain reluctant to use ACE inhibition in these recipients, because of fear of functional decrease in renal perfusion, especially in the setting of renal transplant artery stenosis. To study the long-term effects of RAS blockade we used the established Fisher to Lewis (F-L) model for CRTF, which mirrors the progressive changes seen in humans. Studies in our lab and by others showed that RAS blockade in the F-L model prevents proteinuria, glomerulosclerosis and hypertension. However, when treated for 34 weeks with RAS blockade, renal arteries developed severe intimal hyperplasia. This effect was specific for Fisher rats. Syngrafted Fisher rats treated with ACE inhibition developed intimal hyperplasia, but allografting significantly aggravated it. Fisher rats have a four times higher renal ACE activity, compared with the Lewis rat. This is comparable to the human DD/II genotype differences in ACE activity. Renal transplant patients with the DD genotype may be more vulnerable for vascular changes when treated with RAS blockade.
[Back to top] Viral and Cellular Cytokines as
Therapeutic Targets in AIDS-Related Lymphoproliferative Disorders
Since the advent of highly active antiretroviral therapy (HAART) and its widespread use, the incidence of AIDS-defining illnesses has decreased dramatically, leading to a much longer survival of patients. Despite some exciting new leads, non- Hodgkin's lymphoma (NHL) remains a fatal malignancy for the vast majority of patients with acquired immunodeficiency syndrome (AIDS). Multiple molecular pathways appear to operate in AIDS lymphomagenesis and some may preferentially be associated with specific malignant histopathologic categories or anatomic sites of origin. AIDSassociated lymphomas share several features, including B-cell lineage derivation, diffuse aggressive histology, and frequent origin from or involvement of extranodal sites. Recently, high-grade primary effusion lymphomas (PEL) have been reported in patients with advanced AIDS. PEL is recognized as a distinct clinicopathologic entity associated with Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8). KSHV genes are likely to contribute to the neoplastic phenotype of PEL cells that require cytokines and factors from the host or encoded by the virus for growth in vivo. KSHV is also thought to dramatically affect the incidence, type, and course of multicentric Castleman's disease, another lymphoproliferative disorder over-represented in patients with AIDS. This review summarizes the current knowledge of autocrine growth factor loops and angiogenic factors that are involved in the pathogenesis of KSHV-related lymphoproliferative disorders in AIDS. Deregulated cytokines may represent potential targets of novel therapeutic strategies.