Journal Article

Sildenafil ameliorates right ventricular early molecular derangement during left ventricular pressure overload

Imai, Yousuke, Kariya, Taro, Yamada, Yoshitsugu, Takimoto, Eiki, Iwakiri, Masaki

2018

Overview

Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Anesthesiology / Animals / Aorta / Biology and Life Sciences / Calcineurin / Calcineurin - metabolism / Cardiomegaly - drug therapy / Cardiomegaly - pathology / Cardiomegaly - physiopathology / Cardiovascular Agents - pharmacology / Cardiovascular diseases / Cellular signal transduction / Complications and side effects / Coronary artery disease / Coronary vessels / Crosstalk / Cyclic GMP / Dexamethasone / Dexamethasone - pharmacology / Diabetes / Disease / Disease Models, Animal / Dosage and administration / Drug therapy / Extracellular signal-regulated kinase / Extracellular Signal-Regulated MAP Kinases - metabolism / Gene expression / Guanosine / Heart diseases / Heart failure / Heart Ventricles - drug effects / Heart Ventricles - pathology / Heart Ventricles - physiopathology / Hemodynamics / Hemodynamics - drug effects / Hemodynamics - physiology / Hypertension / Hypertrophy / Hypoxia / Inflammation / Inhibition / Macrophages - drug effects / Macrophages - pathology / Macrophages - physiology / Male / Medical research / Medicine / Medicine and Health Sciences / Mice, Inbred C57BL / Myocardium / Phosphodiesterase / Phosphodiesterase 5 Inhibitors - pharmacology / Prognosis / Pulmonary hypertension / Research and Analysis Methods / Risk factors / Rodents / Signal transduction / Signaling / Sildenafil / Sildenafil Citrate - pharmacology / Studies / Surgery / Transcription activation / Vasodilation / Ventricle / Ventricular Dysfunction - drug therapy / Ventricular Dysfunction - pathology / Ventricular Dysfunction - physiopathology / Ventricular Function, Left - drug effects / Ventricular Function, Left - physiology / Ventricular Function, Right - drug effects / Ventricular Function, Right - physiology / Ventricular Pressure - drug effects / Ventricular Pressure - physiology