The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The present review provides an update on the role of the H-, K- and N-Ras genes and their related pathways in cardiac diseases. We focus on cardiac hypertrophy and heart failure, where Ras has been studied the most. We also review other cardiac diseases, like genetic disorders related to Ras. The scope of the review extends from fundamental concepts to therapeutic applications. Although the three Ras genes have a nearly identical primary structure, there are important functional differences between them: H-Ras mainly regulates cardiomyocyte size, whereas K-Ras regulates cardiomyocyte proliferation. N-Ras is the least studied in cardiac cells and is less associated to cardiac defects. Clinically, oncogenic H-Ras causes Costello syndrome and facio-cutaneous-skeletal syndromes with hypertrophic cardiomyopathy and arrhythmias. On the other hand, oncogenic K-Ras and alterations of other genes of the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, like Raf, cause Noonan syndrome and cardio-facio-cutaneous syndromes characterized by cardiac hypertrophy and septal defects. We further review the modulation by Ras of key signaling pathways in the cardiomyocyte, including: (i) the classical Ras-Raf-MAPK pathway, which leads to a more physiological form of cardiac hypertrophy; as well as other pathways associated with pathological cardiac hypertrophy, like (ii) The SAPK (stress activated protein kinase) pathways p38 and JNK; and (iii) The alternative pathway Raf-Calcineurin-Nuclear Factor of Activated T cells (NFAT). Genetic alterations of Ras isoforms or of genes in the Ras-MAPK pathway result in Ras-opathies, conditions frequently associated with cardiac hypertrophy or septal defects among other cardiac diseases. Several studies underline the potential role of H- and K-Ras as a hinge between physiological and pathological cardiac hypertrophy, and as potential therapeutic targets in cardiac hypertrophy and failure. Graphic abstract

BackgroundSystemic Lupus Erythematosus (SLE) is a devastating autoimmune disease that affects women to men at a ratio of 9:1 and is predominant in those of African ancestry. In SLE, the presence of autoantigens results in aberrant immune activation leading to systemic inflammation that predominantly affects the brain, kidneys, blood, and skin. Current guidelines recommend treatment with immunosuppressive drugs like prednisone, cyclophosphamide, azathioprine, and even some antimalarial drugs [1,2]. However, such drugs have limited efficacy, and result in toxic side effects. Therefore, research into the mechanism of the pathogenesis of SLE in order to identify novel therapies is important.Autoantibodies generated in SLE induce influx of neutrophils to different sites of the body. Neutrophils are the body's first line of defense against pathogens and are the most abundant leukocytes in the blood stream. The normal percentage of neutrophils (50%) can increase to 80% on site of a bacterial infection and detection of tissue inflammation. Neutrophils utilize various mechanisms of defense including phagocytosis, nicotinamide adenine dinucleotide phosphate (NADPH) oxidative burst, as well as the release of reactive oxidative species (ROS) and enzymes. More recently, it was discovered that dying neutrophils release 'spider web' like chromatin fibers called neutrophil extracellular traps (NETs). The release of NETs by activated neutrophils is known as NETosis [3]. These NETs are constructed of decondensed chromatin, histones, granules, and components with bactericidal activity. Antimicrobial enzymes such as myeloperoxidase (MPO), neutrophil elastase (NE), cathelicidins like LL-37, histones, proteinase 3, cathepsin, lactoferrin, or gelatinase are expelled with NETs, enabling them to entrap, inhibit, and kill invading pathogens in an extracellular manner, rather than the canonical method of phagocytosis [3,4].

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