Current Pharmaceutical Design - Volume 17, Issue 18, 2011

Cardiovascular disease is the most common cause of morbidity and mortality in the developed countries, and it accounted for over 600,000 deaths (25% of total mortality) in the U.S. in 2006 [1]. However, despite significant progress in the treatment of cardiovascular diseases, the mortality rate from heart failure still remains very high. Because cardiac hypertrophy is associated with most forms of heart failure, the mechanisms and related therapies for cardiac hypertrophy have remained a central focus of basic and clinical research [2, 3]. Cardiovascular pharmacology is a rapidly developing field with numerous new cardiovascular drugs continually being discovered, and being tested in preclinical studies and clinical trials. In this issue, we will review novel therapies that are on the horizon for the treatment of cardiac hypertrophy and heart failure. Review of these new and emerging pharmacological therapies will not only be interesting, but also will be important for clinical practice. Although complete list of all novel pharmacological therapies is not possible, this review series compile those therapies that hold promise in the near future. Specialists in various fields will contribute their expertise, experience and knowledge on current and emerging cardiovascular pharmacological therapies. Leading off the series, Xia and Vanhoutte, an internationally renowned authority on nitric oxide, will review current status of nitric oxide (NO) inhibition for hypertension and cardiac hypertrophy. They will specifically focus on the role of NO in ischemic myocardial protection with emphasis on its contribution to ischemic pre-and post-conditioning cardioprotection. Singh and Kang will review emerging therapies to inhibit apoptosis in cardiovascular diseases. We will discuss what is currently known about the molecular mechanisms of cardiac apoptosis, and review the potential uses of anti-apoptotic therapies for heart failure. Wu-Wong will review our current understanding of vitamin D signaling in cardiovascular diseases. She will discuss preclinical and clinical studies that support (or argue against) the potential use of vitamin D therapy for left ventricular hypertrophy and heart failure, as well as its broad use for end stage renal disease and vascular diseases. Yan and Morgan, experts on pharmacological therapy for heart failure, will review the current knowledge of the neuregulin 1 (NRG1) and eukaryotic ribosome biogenesis protein 1 (Erb1) signaling in the heart and discuss the potential use of NRG1s as novel therapy for heart failure. Ayogi and Matsui will review the role of phosphatidylinositol 3-kinases (PI3K) signaling in the treatment of cardiac hypertrophy and heart failure. They will discuss the reciprocal regulation of PI3K, serine/threonine protein kinase Akt/PKB and the mammalian target of rapamycin (mTOR) in cardiomyocytes and their association with cardiac disease. For our final review in the series, Kim and Lee will review the role of nanotechnology in medicine. Particularly, they will discuss several novel strategies to use nanomaterial-based diagnosis and therapy in cardiovascular and neurovascular diseases.

Nitric oxide (NO) is produced in almost all tissues and it exerts a variety of biological actions under both physiological and pathological conditions. It is synthesized by three distinct enzymes: endothelial (eNOS), neuronal (nNOS) and inducible (iNOS) nitric oxide synthases. NO is a cardioprotective mediator in powerful cardioprotective processes such as pre- and post-conditioning ischemia; they operate largely in a NO-dependent manner. However, the activity of different NOSs isoforms as well as, the bioavailability of NO can be affected by a variety of disease conditions (in particular diabetes) and pathological situations associated with significantly elevated levels of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). These adversely affect NO-signaling, as well as the efficacy and safety of treatments with NO or NO-containing agents. This brief review focuses on the role of NO in ischemic myocardial protection with emphasis on its contribution to ischemic pre-and post-conditioning cardioprotection. The impact of pathologic conditions on NO bioavailability and NO-signaling and its potential means for improvement, will also be discussed.

Apoptosis or progress of programmed cell death is a tightly regulated process which plays an important role in various cardiovascular diseases particularly in myocardial infarction, reperfusion injury, and heart failure. Over the past two decades, investigations of several pathways have broadened our understanding of programmed cell death. Many anti-apoptotic interventions have targeted ischemia- reperfusion, however only a limited number have been considered at the chronic stage of heart failure. Endogenous inhibitors, caspase inhibitors, PARP-1 inhibitors, as well as various other agents have been implicated as anti-apoptotic interventions. This review summarizes the apoptotic pathways associated with heart failure, discusses the current anti-apoptotic interventions available and reviews the clinical implications.

Vitamin D3 is made in the skin, modified in the liver to form 25(OH)D, and then further hydroxylated in the kidney to form the active hormone, 1,25-dihydroxyvitamin D3 (calcitriol). Calcitriol binds to and activates the vitamin D receptor (VDR), a nuclear receptor, to regulate numerous downstream signaling pathways in different cells and tissues. Emerging evidence suggests that VDR plays an important role in modulating cardiovascular, immunological, metabolic and other functions. Data from preclinical, epidemiological and clinical studies have shown that deficiency in VDR activation is associated with an increased risk for cardiovascular disease (CVD). Results from interventional trials using either nutritional vitamin D or VDR agonists (VDRAs) support the idea that VDR activation is beneficial for improving the underlying factors of CVD such as hypertension, endothelial dysfunction, atherosclerosis, vascular calcification, cardiac hypertrophy and progressive renal dysfunction. Furthermore, a majority of chronic kidney disease (CKD) patients die of CVD and VDRA therapy is associated with a survival benefit in both pre-dialysis and dialysis CKD patients. Most of the studies measured serum 25(OH)D as an indication for vitamin D deficiency, which does not truly reflect the VDR activation status. Although VDR plays an important role in regulating cardiovascular function and VDRAs may be potentially useful for treating CVD, at present VDRAs are not indicated for the treatment of CVD.

Neuregulin1 proteins (NRG1s) are epidermal growth factor (EGF) family members which are ligands for the ErbB receptor tyrosine kinases (RTKs). A decade of research has revealed that the NRG1-ErbB signaling is essential for the cardiac development and pivotal for maintaining the physiological function of the adult heart. The first evidence regarding the protective effect of the ErbB2 signaling in the adult heart came from clinical trials in breast cancer patients using Trastuzumab, a monoclonal antibody that blocks the ErbB2 receptor. The incidence of the New York Heart Association (NYHA) class III/IV heart failure increased five-fold in patients treated concurrently with chemotherapy drug doxorubicin and Trastuzumab compared to those treated with doxorubicin alone. Subsequent studies further show that stimulation of the ErbB2 signaling by NRG1s improves cardiomyocyte survival, growth and proliferation, maintains cardiac myofibril structure, counterbalances excessive β-adrenergic signaling and promotes angiogenesis in the heart. Injections of recombinant NRG1s improve cardiac function in animal models with myocardial infarction, doxorubicin, viral infection or pacing -induced heart failure. Recent clinical trials show that NRG1s are effective for improving the cardiac function in heart failure patients. These results suggest that NRG1s may become a new drug for the treatment of heart failure. NRG1s stimulate RTKs. This is different from Beta-blockers, ACE inhibitors (Angiotensin-Converting Enzyme) and Angiotensin II receptor blockers which inhibit the excessive activation of G-protein coupled receptors (GPCRs). A clear understanding of how NRG1-ErbB signaling regulates cardiac function is essential for successful use of NRG1s for heart failure. Here, we review the current knowledge of the NRG1-ErbB signaling in the heart and discuss the potential use of NRG1s as novel therapy for heart failure.

Heart failure, a major symptom in the progression of cardiac hypertrophy, is a critical risk factor for cardiac death. A large body of research has investigated cardioprotective mechanisms that prevent or minimize hypertrophy, identifying a variety of specific peptide hormones, growth factors, and cytokines with cardioprotective properties. Recent investigation of the downstream effector pathways for these growth factors has identified molecules involved in the progression of cardiac hypertrophy and heart failure, including phosphoinositide 3-kinase (PI3K), Akt and mammalian target of rapamycin (mTOR). Using genetically modified transgenic or knockout mice and adenoviral targeting to manipulate expression or function in experimental models of heart failure, several investigators have demonstrated that the PI3K-Akt pathway regulates cardiomyocyte size, survival, angiogenesis, and inflammation in both physiological and pathological cardiac hypertrophy. In this review, we discuss the reciprocal regulation of PI3K, Akt and mTOR in cardiomyocytes and their association with cardiac disease.

Nanomedicine is using nanotechnology in the medical application, which could range from medical use of nanomaterials in drug delivery and bio-imaging to development of nano-scale devices and sensors for diagnosis and therapy. Nanomedicine could also include methods to evaluate nanomaterials solely to ensure safe use through careful monitoring for potential toxicity. In this review, we will outline some of the potential uses of nanotechnology in different fields of medicine with special emphasis on cardiovascular diseases and stroke, based on pathophysiologic basis. We will also review some of the known nanomaterials that are already being utilized in diagnosis and treatment, commonly the FDA approved nanomaterials and others that have demonstrated to be promising in clinical applications. Finally, we will discuss the potential limitations of using nanotechnology in medical applications. Since nanomedicine is now emerging and still in development, this review is not intended as a comprehensive or conclusive overview of nanomedicine. Instead, we hope to provide examples of what are available currently, and to demonstrate the enormous potentials of nanomedicine in order to meet the unresolved needs and new challenges of medicine.

The targeted delivery of theranostic agents to the cancer cells is one of the major challenges and an active field of research in the development of cancer chemotherapeutic approaches. Theranostic metallic nanoparticles (TMNPs) have garnered increasing attention in recent years as a novel tool for theranostic application such as imaging, diagnosis, and therapeutic delivery of active agents to tumour specific cells. This paper attempts to unveil the multidimensional theranostic aspects of multifunctional metallic nanoparticles (MNPs) including passive and active targeting (HER2, Folate, Angiogenesis etc.) as well as the RES escaping approach. Special attention is given to the theranostic application of MNPs in oncology. Patents issued by the US office in this nanotechnological arena are also included emphasising the importance of MNPs in current cancer treatment/imaging research scenario. Keeping in mind the blooming research in clinical application directed nanotechnology; toxicity concerns related with MNPs are. also discussed, in element.

Plants belonging to the genus Maytenus (Celastraceae) are routinely used in folk medicine in Brazil and other countries to treat a variety of illnesses, the most common of which are gastric disorders. Several studies have reported on the importance of these biological effects, and the chemical substances, mostly terpenoids and flavonoid glycosides, responsible for them. This review summarizes the ethnopharmacological, chemical and pharmacological knowledge of plants of the Maytenus genus, with particular emphasis on those growing in Brazil.