The Ubiquitin Ligase WWP1 Contributes to Shifts in Matrix Proteolytic Profiles and a Myocardial Aging 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 aging 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. However, at 8 weeks of age, LV mass increased by over two-fold, E/A fell (impaired passive filling), and E/E’ was lower and IVRT prolonged (impaired LV relaxation) - all p<0.05. Collagen percent area increased by over two-fold and fibrillar collagen expression (rtPCR) by over 1.5 fold (p<0.05) with WWP1 O/E. WWP1 with an anti-WWP1 antibody could be identified in isolated cardiac fibroblasts with WWP1 increased by over two-fold in O/E fibroblasts (p<0.05).

Conclusion. Inducing WWP1 expression caused LVH, preserved systolic function, but impaired diastolic dysfunction, consistent with the HFpEF phenotype. Targeting the WWP1 pathway may be a novel therapeutic target for this intractable form of HF associated with aging.