vivit-peptide and Cardiomegaly

Cardiovascular disease is the major cause of death in industrialized nations. Targeted intervention in calcineurin, a calmodulin-dependent, calcium-activated phosphatase and its substrate, nuclear factor of activated T cells (NFAT), was demonstrated to be effective in the treatment of cardiovascular diseases. Although effective in the disruption of calcineurin phosphatase activity, cyclosporin A (CsA) and FK506 also resulted in undesired side effects and toxicity, prompting the discovery of VIVIT, a novel peptide inhibitor. VIVIT selectively and potently inhibits calcineurin/NFAT interaction, but does not compromise calcineurin phosphatase activity and non-NFAT-mediated signaling. VIVIT displays a favorable therapeutic profile as a potential drug candidate and constitutes a useful tool in exploring calcineurin-NFAT functionality. This review describes the development of VIVIT peptide as a selective NFAT inhibitor and its application as a therapeutic agent in cardiovascular disorders including cardiac hypertrophy, restenosis, atherosclerosis, and angiogenesis.

Topics: Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Cardiovascular Diseases; Humans; NFATC Transcription Factors; Oligopeptides

Background The development of pathological cardiac hypertrophy involves the coordination of a series of transcription activators and repressors, while their interplay to trigger pathological gene reprogramming remains unclear. NULP1 (nuclear localized protein 1) is a member of the basic helix-loop-helix family of transcription factors and its biological functions in pathological cardiac hypertrophy are barely understood. Methods and Results Immunoblot and immunostaining analyses showed that NULP1 expression was consistently reduced in the failing hearts of patients and hypertrophic mouse hearts and rat cardiomyocytes.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cardiomegaly; Echocardiography; Gene Deletion; Humans; Immunoprecipitation; Mice; Mice, Knockout; Mice, Transgenic; Myocytes, Cardiac; NFATC Transcription Factors; Oligopeptides; Phosphoric Monoester Hydrolases; Rats; Rats, Sprague-Dawley; Repressor Proteins; Transcription, Genetic

Interferon regulatory factor 8 (IRF8) is known to affect the innate immune response, for example, by regulating the differentiation and function of immune cells. However, whether IRF8 can influence cardiac hypertrophy is unknown. Here we show that IRF8 levels are decreased in human dilated/hypertrophic cardiomyopathic hearts and in murine hypertrophic hearts. Mice overexpressing Irf8 specifically in the heart are resistant to aortic banding (AB)-induced cardiac hypertrophy, whereas mice lacking IRF8 either globally or specifically in cardiomyocytes develop an aggravated phenotype induced by pressure overload. Mechanistically, we show that IRF8 directly interacts with NFATc1 to prevent NFATc1 translocation and thus inhibits the hypertrophic response. Inhibition of NFATc1 ameliorates the cardiac abnormalities in IRF8(-/-) mice after AB. In contrast, constitutive activation of NFATc1 nullifies the protective effects of IRF8 on cardiac hypertrophy in IRF8-overexpressing mice. Our results indicate that IRF8 is a potential therapeutic target in pathological cardiac hypertrophy.

Topics: Animals; Calcineurin; Cardiomegaly; Cardiomyopathy, Hypertrophic; Female; Humans; Interferon Regulatory Factors; Male; Mice; Mice, Knockout; Mice, Transgenic; NFATC Transcription Factors; Oligopeptides; Signal Transduction

The activation of the calcineurin-nuclear factor of activated T cells cascade during the development of pressure-overload cardiac hypertrophy has been previously reported in a number of studies. In addition, numerous pharmacological studies involving calcineurin inhibitors such as FK506 and cyclosporine A have now demonstrated that these agents can prevent such hypertrophic responses in the heart. However, little is known regarding the roles of the calcineurin downstream effector--nuclear factor of activated T cells. Our present study has further examined the roles of nuclear factor of activated T cells in pressure-overload cardiac hypertrophy by employing a recently developed cell-permeable nuclear factor of activated T cells inhibitor peptide. Rat hearts were subjected to pressure overload attributable by 4 weeks of aortic banding, and then treated with this cell-permeable nuclear factor of activated T cells inhibitor peptide and a control peptide. Treatment with the inhibitor was found to significantly decrease the heart weight/body weight ratio, the size of cardiac myocytes, and the serum brain natriuretic peptide and atrial natriuretic peptide levels. These results suggest that nuclear factor of activated T cells functions in a key role in the development of cardiac hypertrophy during pressure overload. Inhibition of nuclear factor of activated T cells by a specific inhibitor peptide is a suitable method for characterization of the molecular mechanisms underlying cardiac hypertrophy as well as in the search for new promising therapies for disease.

Topics: Animals; Aorta, Abdominal; Atrial Natriuretic Factor; Calcineurin; Cardiomegaly; Cell Membrane Permeability; Male; Natriuretic Peptide, Brain; NFATC Transcription Factors; Oligopeptides; Rats; Rats, Wistar; Signal Transduction; Ventricular Pressure