Cardiovascular & Haematological Disorders - Drug Targets - Volume 13, Issue 2, 2013

SERPINA1, α-antitrypsin (AAT) is an acute phase protein, a member of the serpin (serine protease inhibitor) super family and one of the most abundant protease inhibitors in the circulation. The clinical importance of AAT is emphasized in persons with inherited AAT deficiency who exhibit high risk of developing early onset pulmonary emphysema, neonatal hepatitis, liver cirrhosis, which may appear at any age, and in rare cases panniculitis and vasculitis. The most common and severe AAT deficiency is associated with the Z (Glu342 to Lys) mutation. It is also well established that Z AAT deficiency results from the polymerization and accumulation of the misfolded AAT protein. Consequently, low levels of circulating Z AAT are assumed to be inadequate to neutralize elastolytic activity and to prevent lung tissue damage. Novel studies, however, are expanding the link between AAT and human diseases. Associations are shown between reduced AAT levels and HIV type 1 infection, hepatitis C infection, diabetes mellitus, vasculitis, panniculitis and other diseases. Given the importance of the protease/antiprotease imbalance in causing emphysema, augmentation of circulating AAT is used as a specific therapy for patients with AAT deficiency-related emphysema but not for those with liver diseases. According to the novel findings, therapy with AAT possesses antiinflammatory and immuno-modulatory effects across a broad spectrum of experimental models of systemic and local inflammation. Hence, in this article we will discuss putative new directions for the clinical use of therapy with AAT.

Serpins in the mammalian body are highly potent serine protease inhibitors which modulate both thrombotic and thrombolytic pathway activation, with direct and indirect crosstalk with immune and inflammatory pathways. In this review, we discuss mammalian and viral serpins as regulators of coagulation and inflammation. We focus first on the thrombotic and thrombolytic serine proteases and known interactions between these protease cascades and elements of the innate immune response. Serpin-mediated regulation of the thrombotic pathway is then discussed, with emphasis on those serpins that have been evaluated as potential new drugs. Finally the potential of viral serpins that target the coagulation and thrombolytic cascades as potential therapeutics for anti-inflammatory properties is discussed from basic molecular activity to studies in animal models. The studies discussed range from thrombosis and hemorrhage to vascular disease and transplant rejection and finally to sepsis and clinical studies in humans. In conclusion, these unique proteins, the serpin family, now have demonstrated therapeutic potential for a wide variety of inflammatory diseases in both animal and human studies and represent a new approach for drug development.

Acute cardiovascular syndromes such as myocardial infarction and stroke are a major cause of death in the Western society and are generally caused by rupture of an atherosclerotic plaque. Treatment of atherosclerosis, the main underlying cause of acute cardiovascular syndromes, is still inadequate for most of the patients. Therefore, there is a need for new therapeutic strategies in addition to the existing lipid-lowering drugs such as statins. Lipid accumulation, inflammation and matrix degradation are generally considered key processes in the pathogenesis of atherosclerosis and that of plaque rupture. Furthermore, apoptosis or programmed cell death of plaque cells, depending on the disease stage, is thought to be of importance in the development and progression of atherosclerosis and the incidence of acute cardiovascular syndromes. Serine protease inhibitors or so-called serpins have been demonstrated to be involved in both the induction and inhibition of apoptosis and may thus be of interest as therapeutics in cardiovascular diseases such as atherosclerosis. In this review, we will discuss the current knowledge on the role of serpins in cardiovascular diseases with particular emphasis on apoptotic cell death and the potential therapeutic applications.

Serine protease inhibitors (Serpins) play an important role in regulating a wide array of diverse biological activities, representing up to 2-10% of circulating plasma proteins. The serpin suicide inhibitors regulate coagulation (thrombosis and thrombolysis), neurotrophic factors, hormone transport, complement and inflammation, angiogenesis, hormone transport, and blood pressure among many other biological reactions. Select serpins have been associated with progression or remission of selected cancers, making them valuable for therapeutic or diagnostic use. Plasminogen activator inhibitor-1 (PAI-1), the main regulator of thrombolysis, has the potential to either reduce or accelerate tumor growth but blockade of PAI-1 has recently been reported to reduce cancer cell migration, proliferation and survival through modulating the function of urokinase-type plasminogen activator receptor. Maspin is a non-inhibitory serpin, that increases cancer cell sensitivity to apoptosis and inhibits cancer cell migration thus providing a serpin that blocks tumor gorwth. Pigment epithelium derived factor (PEDF) has potent anti-angiogenesis activity and also promotes cancer cell apoptosis. Among other serpins, the mammalian serpin, neuroserpin, and the myxomavirus derived serpin, Serp-1 are under investigation in our lab for their potential tumor-suppressive functions. Further study on the efficacy and mechanisms of serpin mediated anti-cancer activity is warranted in order to develop new serpin-based approaches in cancer therapy.

The most common of the primary immunodeficiency diseases are those that involve inadequate antibody production. The characteristic presentation of these disorders is recurrent sinopulmonary infections. An arrest in B cell development at the pre-B cell stage leads to agammaglobulinemia and an insignificant number of B cells. X-linked agammaglobulinemia is the most common of these developmental arrests while the autosomal recessive agammaglobulinemias comprise a small minority of the total cases. Likewise, the most common form of the hyper-IgM syndromes (CD40 ligand deficiency) is X-linked. Of the autosomal recessive forms, CD40 deficiency is basically identical to the X-linked form in its clinical phenotype where, in addition to inadequate antibody production, there is defective T cell signaling through the CD40-CD40L interaction. Aside from CD40 deficiency, the other recessive forms of hyper-IgM syndrome have adequate T cell function. IgA deficiency is the most common and the most benign of the B cell disorders. Common variable immunodeficiency is diverse in its presentation and clinical course. The pathophysiology of this disease is multifactorial and frequently ill defined, often making it a diagnosis of exclusion. A working knowledge of identifiable PIDDs is essential in both recognizing when to suspect immunodeficiency and making a diagnosis.

This review summarizes our current knowledge of plasminogen activator inhibitor (PAI-1) deficiency and proposes some novel treatments for this condition. PAI-1 is a fast acting inhibitor of tissue and urokinase plasminogen activators (tPA and uPA). PAI-1 controls/slows clot lysis triggered by tPA activated plasminogen. PAI-1 deficiency was once considered to be an extremely rare disorder characterized by frequent and prolonged bleeding episodes. PAI-1 deficiency is now thought to be more frequent than initially reported and is known to be caused by mutations in the PAI-1 gene that produce a dysfunctional PAI-1 protein or slow the secretion of PAI-1 into the circulation. PAI-1 deficiency is characterized by hyperfibrinolysis that results in frequent bleeding episodes. Patients with this condition form normal blood clots that are quickly lysed by unopposed tPA-activated plasmin. Spontaneous bleeding is rare in PAI-1 deficient patients, but moderate hemorrhaging of the knees, elbows, nose, and gums can be triggered by mild trauma. Additionally, prolonged bleeding after surgery is common and menstrual bleeding may be severe. Moderate PAI-1 deficiency is associated with a lifelong bleeding tendency, but severe deficiencies can be life-threatening. The diagnosis of this disorder remains challenging due to the lack of a clear definition of PAI-1 deficiency as well as a lack of standardized tests. Patients with mild PAI-1 deficiency may be treated with antifibrinolytic agents (ε-aminocaproic acid or tranexamic acid); however, not all patients respond well to these treatments. These patients may be treated with wild-type PAI-1; however, this molecule quickly converts into its inactive form. We propose to use PAI-1 with an extended half-life to treat these patients.

Patients with unstable angina pectoris/non-ST-elevation myocardial infarction (NSTEMI) should be treated with dual antiplatelet therapy with the use of aspirin plus either clopidogrel, prasugrel, or ticagrelor depending on the clinical circumstances as discussed in this article. If ticagrelor is used, the dose of aspirin must not exceed 100 mg daily. Prasugrel must not be used in patients with a history of stroke or transient ischemic attack. Platelet glycoprotein IIb/IIIa inhibitors should not be used as part of triple antiplatelet drug therapy if there is an increased risk for bleeding or in non-high-risk patients such as those with a normal baseline cardiac troponin level, nondiabetics, and those aged 75 years and older in whom potential benefit may be significantly offset by the potential risk of bleeding. Clinical trial data in patients with acute coronary syndromes do not support the use of intravenous cangrelor or oral voraxapar in the treatment of these patients.

Cardiovascular disease is the number one cause of death worldwide. A major underlying cause of cardiovascular disease is atherosclerosis – a chronic inflammatory disease of the large arteries. Despite substantial advances over the past few decades, our understanding of the molecular mechanisms that link cardiovascular risk factors to the development and progression of atherosclerosis is incomplete. The endoplasmic reticulum (ER) is a membranous organelle found in all eukaryotic cells that is responsible for protein processing and lipid biosynthesis. In recent years it has become evident that disruptions in ER function are associated with a number of human diseases including atherosclerosis. In this review we examine the potential role of endoplasmic reticulum stress in the initiation and progression of atherosclerosis and discuss possible strategies to target this pathway toward the development of new anti-atherogenic therapies.

A chronic increase in reactive oxygen species (ROS) plays a critical role in the development and progression of cardiac remodeling associated with heart failure. Oxidative stress is indeed increased in heart failure, hypertension, cardiac fibrosis and hypertrophy. In vitro exposure of cardiac fibroblasts to superoxide anion stimulates their proliferation by increasing the production of transforming growth factor-β1 (TGF-β1), a potent fibrogenic cytokine. TGF-β1 plays an important role in cardiac development, cardiac hypertrophy, ventricular remodeling and the early response to myocardial infarction. In this review the role of TGF-β1 and ROS in the production and deposition of collagens by cardiac fibroblasts and in the induction of gene expression in relation to the development of myocardial fibrosis and to myocardial tissue repair will be discussed.