Cyclic guanosine monophosphate is an important regulator of signal transduction in the cardiovascular system. It is synthesized by soluble guanylyl cyclase in response to stimulation by nitric oxide, and is cleared by phosphodiesterases, including PDE5A. Expression of PDE5A has been found in cardiomyocytes. Recently our lab has shown that PDE5 inhibition by drugs such as sildenafil can suppress chronic beta-adrenergic induced right ventricular hypertrophy. Furthermore, we have additional preliminary studies suggesting the RhoA/rho kinase pathway is involved in the PDE5A inhibition hypertrophy modulation in the right ventricle.
In Specific Aim #1 we will show that right ventricular hypertrophy induced by pulmonary arterial banding is prevented by PDE5A inhibition and involves the RhoA/rho kinase pathway.
Specific Aim #2 will show that RhoA/rho kinase is important in the hypertrophic response of right ventricular cardiomyocytes to after load stress and can be prevented by PDE5A inhibition. These studies will add broader understanding to the mechanisms underlying right ventricular hypertrophy and failure and will potentially offer novel therapeutic targets for right heart failure and pulmonary hypertension.
| Gebska, Milena A; Stevenson, Blake K; Hemnes, Anna R et al. (2011) Phosphodiesterase-5A (PDE5A) is localized to the endothelial caveolae and modulates NOS3 activity. Cardiovasc Res 90:353-63 |
| Robbins, Ivan M; Newman, John H; Johnson, Roger F et al. (2009) Association of the metabolic syndrome with pulmonary venous hypertension. Chest 136:31-36 |
| Hemnes, Anna R; Robbins, Ivan M (2009) Sildenafil monotherapy in portopulmonary hypertension can facilitate liver transplantation. Liver Transpl 15:15-9 |
| Hemnes, Anna R; Zaiman, Ari; Champion, Hunter C (2008) PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation. Am J Physiol Lung Cell Mol Physiol 294:L24-33 |
