PDE5 Inhibition Modulates Right Ventricular Failure

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): 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.