Current Pharmaceutical Design - Volume 15, Issue 24, 2009

Ischemic cardiovascular diseases, such as coronary artery disease and peripheral arterial disease, are significant medical problems worldwide and, in particular, coronary artery disease remains a major cause of morbidity and mortality in the Western world. Despite significant progress in revascularization procedures, a substantial number of patients with ischemic cardiovascular diseases are either not candidates for these procedures or can be only partially revascularized. Nearly a decade ago, Asahara et al. [1] identified endothelial progenitor cells (EPCs) from circulating adult peripheral mononuclear cells. Since then, accumulating evidence indicates that bone marrow- and peripheral blood-derived progenitor/stem cells have therapeutic potential for the treatment of patients with cardiovascular diseases such as peripheral arterial diseases and myocardial ischemia. Furthermore, therapeutic application of human pluripotent stem cells such as embryonic stem (ES) and pluripotent stem (iPS) cells for cardiovascular diseases has been investigated recently. The aim of this issue is to provide a review of the basic and clinical advances in therapeutic angiogenesis and regeneration in cardiovascular diseases. In the current issue of Current Pharmaceutical Design, therapeutic angiogenesis and regeneration by progenitor/stem cells are carefully reviewed by the experts who have contributed in this field of research. In the first article by Tanaka and Sata [2], recent findings on the role of vascular progenitor cells, such as EPCs and smooth muscle cell progenitor cells (SMPCs), in cardiovascular disease are overviewed. Matoba and Matsubara [3], who previously conducted TACT study, reported the efficacy and long-term outcome of therapeutic neovascularization by autologous bone marrow cells implantation for PAD patients. In addition, we discussed the abnormalities of EPCs in patients with connective tissue diseases (CTDs) such as systemic scleroderma (SSc) and systemic lupus erythematosus (SLE), and reported clinical pilot study of autologous cell therapy for critical digit ischemia in patients with CTDs [4]. Murohara et al. [5] reviewed adipose-derived regenerative cells for therapeutic angiogenesis. Shiba et al. [6] discussed the phenotype of human ES and iPS cell-derived cardiomyocytes, the state of preclinical transplantation studies, and potential approaches to overcoming the aforementioned hurdles to clinical application using these stem cells. In the final article by Shimizu et al. [7], cell sheet-based myocardial tissue engineering was reviewed. I wish to thank all the authors for their essential contribution and believe that this issue may be useful for readers working in basic and translational medical science and for clinicians to update information on the trends in the filed of cardiovascular diseases.

It is a widely accepted view that vascular repair results from migration and proliferation of adjacent vascular cells. On the other hand, accumulating evidence suggests that bone marrow cells can give rise to endothelial-like cells and smooth muscle-like cells that potentially contribute to vascular healing, remodeling and lesion formation under physiological and pathological conditions. However, some recent reports indicated controversial results and cast a doubt on the specificity of the method to detect differentiation of ectopic cells. Here, we overview recent findings on the role of vascular progenitor cells in cardiovascular diseases and provide possible explanation why different conclusions have been drawn from different animal experiments.

Critical limb ischemia (CLI) is a terminal stage of peripheral artery disease (PAD). The number of patients with CLI is increasing, and the disease has a major impact on patients' quality of life. In spite of the marked advances in surgery and interventional angioplasty, a large number of patients require revascularization. To treat these patients, cell based angiogenesis is attracting a great deal of attention as a new strategy. “Therapeutic angiogenesis” is a term that has become widely used in the last decade. Despite negative results in several clinical trials of cytokine-based angiogenesis, cell based therapy produced effective angiogenesis. This cell-based angiogenesis originates from persistent basic research. The first clinical randomized pilot study was reported in 2002. Up to now, more than 30 clinical studies on the use of mononuclear cells or progenitor cells for the treatment have been published. As the prognosis of the patients with CLI is poor, it has been discussed with respect to their safety and feasibility. With the increasing number of treated patients, the accumulated outcomes from these clinical studies are demonstrating this therapy to be reliable. They reveal indications of the stage of the patients with PAD and the timing of treatments. However, clinical data concerning long time prognosis and a standardized protocol have not been discussed sufficiently. This review summarises data from recent clinical outcomes from 17 studies (11 involving BMMNC that included >10 patients, 6 involving PBMNC that included >10 patients) that are treating patients with PAD by autologous cell transplantation.

Vasculopathy in patients with connective tissue diseases (CTDs), including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE), is a serious complication that mainly affects small arteries and capillaries, reduces the blood flow and causes progressive tissue ischemia. Recently, CTD patients have been reported to have abnormalities in circulating endothelial progenitor cells (EPCs); these abnormalities are believed to contribute to the pathophysiology of vasculopathy and to the premature and accelerated development of atherosclerosis in CTD patients. Furthermore, we are currently conducting a clinical pilot study to determine the efficacy of implanting autologous mononuclear cells obtained from the bone marrow and peripheral blood into the ischemic digits or limbs of CTD patients. In this review, we discuss the role of EPCs in the process of neovascularization and in the pathophysiology of CTDs, and we describe a clinical pilot study on the use of autologous cell therapy for treating ischemic digits in patients with CTDs.

Therapeutic angiogenesis is an important means to salvage tissues against severe ischemic diseases in patients with no option for other vascular intervention. A number of recent studies implicated potentials of cell-based therapeutic angiogenesis using autologous bone marrow mononuclear cells, CD34+ cells, peripheral blood mononuclear cells, and so on. Subcutaneous adipose tissues can be harvested by relatively easy methods. Recent studies indicated that adipose tissues contain progenitor cells or regenerative cells that can give rise to several mesenchymal lineages. Moreover, these progenitor cells can release multiple angiogenic growth factors and cytokines/chomokines including vascular endothelial growth factor (VEGF), hypatocyte growth factor (HGF) and chemokine stromal cell-derived factor-1 (SDF-1). The combination of these biological properties of adipose-derived regenerative cells (ADRCs) implicates that autologous adipose tissue will be a useful cell source for therapeutic angiogenesis in the next generation.

Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) can self-renew indefinitely, while maintaining the capacity to differentiate into useful somatic cell types, including cardiomyocytes. As such, these stem cell types represent an essentially inexhaustible source of committed human cardiomyocytes of potential use in cellbased cardiac therapies, high-throughput screening and safety testing of new drugs, and modeling human heart development. These stem cell-derived cardiomyocytes have an unambiguous cardiac phenotype and proliferate robustly both in vitro and in vivo. Recent transplantation studies in preclinical models have provided exciting proof-of-principle for their use in infarct repair and in the formation of a “biological pacemaker”. While these successes give reason for cautious optimism, major challenges remain to the successful application of hESCs (or hiPSCs) to cardiac repair, including the need for preparations of high cardiac purity, improved methods of delivery, and approaches to overcome immune rejection and other causes of graft cell death. In this review, we describe the phenotype of hESC- and hiPSC-derived cardiomyocytes, the state of preclinical transplantation studies with these cells, and potential approaches to overcome the aforementioned hurdles.

Regenerative therapy has currently emerged as one of the most promising treatments for the patients suffering from severe heart failure. Several cell therapies by direct injection have been already clinically performed. However, significant cell loss due to physical strain, primary hypoxia or cell wash-out has become problematic. To overcome this obstacle, tissue engineered myocardial patch transplantation has been examined as the second generation cell therapy. Furthermore several research groups have challenged to engineer pulsatile myocardial tissues/organs using beating cardiomyocytes. Among several tissue engineering technologies, we have developed cell sheet-based tissue engineering, which utilize two-dimensional (2-D) cell sheets harvested from temperature-responsive culture surfaces and create threedimensional (3-D) tissues by stacking cell sheets without generally utilized scaffolds. Several types of cell sheet-based patches have improved damaged heart function in rat, canine and pig models. Stacked cardiomyocyte sheets simultaneously beat in macroscopic view both in vitro and in vivo and revealed characteristic structures of native heart tissue. As a possible solution for scaling up, multi-step transplantation of triple-layer cell sheets was performed and finally, 10-time transplantations have realized about 1 mm-thick functional myocardial tissue. As further advanced therapy, functional myocardial tubes have been also engineered by wrapping cell sheets. Cell sheet-based tissue engineering should have enormous potential in myocardial tissue regenerative medicine and rescue many patients suffering severe heart failure.

Hypertension is one of the major risk factors for cardiovascular disease. Angiotensin receptor blockers (ARBs) are a class of antihypertensive drugs with established efficacy and favorable safety profile. Telmisartan, a member of the ARB family, holds some additional traits which differentiate it from the rest ARBs. A pivotal role in these characteristics plays its ability to partially activate the peroxisome proliferator activated receptor-γ, which in turn controls a number of metabolism-related genes. Indeed, telmisartan has shown a number of pleiotropic effects in experimental and clinical studies. These include the amelioration of insulin resistance, improvement of lipid profile and favorable fat redistribution. Moreover, telmisartan has been associated with beneficial effects on vascular function, cardiac remodeling and renal function. However, do all these pleiotropic effects translate into clinical benefit? Recent studies have tried to answer this question with promising but not definitive results.

The mechanism is presented whereby simultaneous hydrolysis of two molecules of ATP in the ATP-binding cassette (ABC) exporter protein, Sav 1866, opens a transmembrane channel to pump drug out of the cell and confers drug resistance, e.g., gives rise to methicillin resistant Staphylococcus aureus, MRSA. The proposed mechanism suggests pharmaceutical design strategies for overloading the capacity of two molecules of ATP to open access to the channel for export. Structural homology of Staphylococcus aureus, Sav 1866, to human P-glycoprotein and MRP2, suggests a similar mechanism could be relevant to human carcinoma cells. The transport mechanism utilizes two thermodynamic quantities - ΔGHA, the change in Gibbs free energy for hydrophobic association, and ΔGap, an apolar-polar repulsive free energy for hydration, derived from studies on designed elasticcontractile model proteins (ECMPs). These quantities also allow design of remarkably biocompatible ECMPs as drug delivery vehicles with remarkable control of release profiles and of ECMPs that provide the means of developing pharmaceuticals for blocking multi-drug resistance.