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

Aims. 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.

Methods and Results. 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>0.90) with no difference in LV mass (67+3 vs 75+5, p>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.

Conclusion. 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