The Ubiquitin Ligase WWP1 Contributes to Shifts in Matrix Proteolytic Profiles and a Myocardial Ageing Phenotype with Diastolic Heart Failure

<strong><em>Aims</em></strong>. Ubiquitylation is a key event that regulates protein turnover, and induction of the ubiquitin ligase E3 WWP1 has been associated with age. Left ventricular hypertrophy (LVH) commonly occurs as a function of age and can cause heart failure with a preserved ejection fraction (EF; HFpEF). We hypothesized that overexpression (O/E) of WWP1 in the heart would cause LVH as well as functional and structural changes consistent with the ageing HFpEF phenotype. <strong><em>Methods and Results.</em></strong> Global WWP1 O/E was achieved in mice (n=11) and echocardiography (40 MHz) performed to measure LV mass, EF, Doppler velocities (early-E, late/atrial-A), myocardial relaxation (E’), and isovolumetric relaxation time (IVRT) at 4, 6, and 8 weeks. Age matched wild type animals (n=15) were included as referent controls. LV EF was identical (60+1% vs 60+1%, p&gt;0.90) with no difference in LV mass (67+3 vs 75+5, p&gt;0.25) at 4 weeks. LVH and diastolic dysfunction occurred with WWP1 O/E wherein LV mass increased by over two-fold, E/A fell (impaired passive filling), and E/E’ was lower and IVRT prolonged (impaired LV relaxation). Collagen percent area increased by over two-fold with WWP1 O/E and increased expression of determinants of fibrosis and growth (qPCR) were also concomitantly increased. <strong><em>Conclusion.</em></strong> Inducing WWP1 expression caused LVH with significant diastolic dysfunction, consistent with the HFpEF phenotype. Thus, targeting the WWP1 pathway may be a novel therapeutic target for this intractable form of HF associated with ageing