ABSTRACT
Group II pulmonary hypertension (PH) commonly occurs in the setting of a pressure-overloaded left ventricle (LV) which is also conducive to the development of heart failure with preserved ejection fraction. Population trends and a high prevalence of underlying causative conditions, such as essential hypertension or aortic stenosis, have increased the awareness of the pressure-overloaded LV and associated group II pulmonary hypertension. Patients often exhibit poor exercise tolerance and signs of heart failure indistinguishable from systolic heart failure; but effective medical treatments in this area have been lacking. Recent preclinical work has shed light on how the down-regulated nitric oxide - cyclic GMP pathway (within the myocardium and pulmonary vasculature) contributes to the pathophysiology of these associated conditions. This article will discuss the impact of the nitric oxide - cyclic GMP pathway on the pathogenesis of the pressure-overloaded LV and group II pulmonary hypertension, and will also introduce the potential therapeutic value of modulating this pathway.
Subject(s)
Cyclic GMP/metabolism , Hypertension, Pulmonary/physiopathology , Hypertrophy, Left Ventricular/physiopathology , Nitric Oxide/metabolism , Antihypertensive Agents/therapeutic use , Aortic Valve Stenosis/physiopathology , Cardiomyopathies/physiopathology , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Diastole/physiology , Heart Failure/physiopathology , Heart Failure/therapy , Humans , Hypertension, Pulmonary/drug therapy , Oxidative Stress/physiology , Phosphodiesterase 5 Inhibitors/pharmacology , Signal Transduction/physiology , Stroke Volume/physiology , Systole/physiology , Ventricular Dysfunction, Left/physiopathology , Ventricular Remodeling/physiologyABSTRACT
We have generated the first monoclonal antibodies (MAbs) to Armadillo repeat gene deleted in velo-cardiofacial syndrome (ARVCF), a recently identified Armadillo repeat-containing protein closely related to the catenin p120ctn. Six ARVCF-specific MAbs were characterized for isotype, species cross-reactivity, and utility in assays including immunofluorescence, immunoprecipitation, and Western blotting. All six antibodies were isotyped as IgG1 and several cross-reacted with ARVCF from a variety of species including human, rat, dog, and monkey, but not mouse. Importantly, none of the ARVCF MAbs cross-reacted with p120ctn, despite the high homology between these proteins. MAbs 3B2 and 4B1 were consistently the best in all applications and will provide valuable tools for further study of the role of ARVCF in cells.
