The role of cGMP in the physiological and molecular responses of the right ventricle to pressure overload

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease that is associated with a poor prognosis and results in right heart dysfunction. While pulmonary vascular disease is the obvious primary pathological focus, right ventricular hypertrophy (RVH) and right ventricular (RV) dysfunction are major determinants of prognosis in PAH. Our knowledge about the molecular physiology and pathophysiology of RV hypertrophy and failure in response to pressure overload is still limited, and most data are derived from left heart research. However, the molecular mechanisms of left ventricular remodelling cannot be generalized to the RV, because the right and left ventricles differ greatly in their size, shape, architecture and function. Despite the recent advances in diagnosis and treatment of PAH, little is known about the molecular and cellular mechanisms that underlie the transition from compensatory to maladaptive RV remodelling. The cGMP-phosphodiesterase 5 (PDE5) pathway is one of the extensively studied pathways in PAH, but our knowledge about cGMP-PDE5 signalling in RV pathophysiology is still limited. For this purpose, there is need for animal models that can represent changes in the RV that closely mimic the human situation. The availability of an animal model of pressure-overload-induced RVH (e.g. pulmonary artery banding model) provides us with a valuable tool to understand the differences between adaptive and maladaptive RVH and to explore the direct effects of current PAH therapy on the heart. In this report, we discuss myocardial regulatory effects of cGMP-PDE5 signalling in preclinical models of RV pressure overload for understanding the physiological/pathophysiological mechanisms involved in maladaptive RVH.