Camila F. Villacreses, Heather Doviak, Julia Jacobs, Paige E. Perreault, Lydia E.

Matesic, Francis G. Spinale

Myocardial Induction of Ubiquitin Ligase Shifts Matrix Proteolytic Profiles and

Causes an Advanced Myocardial Aging Phenotype with Diastolic Heart Failure

Background. Ubiquitylation is a key event that regulates protein turnover, and induction
of ubiquitin ligase E3 Wwp1 occurs as a function of age. With aging, LV hypertrophy
(LVH) can cause heart failure with a preserved ejection fraction (EF; HFpEF). We
completed a study that tested the hypothesis that inducible expression of Wwp1 would
cause LVH, changes in determinants of matrix remodeling and indices of diastolic
dysfunction, consistent with the aging HFpEF phenotype.
Methods/Results. Wwp-1 overexpression (Wwp-1exp) was achieved in mice (n=11;
tamoxifen inducible construct) and echocardiography (40 MHz) performed to measure
LV mass, EF, Doppler velocities (early-E, late/atrial-A), Doppler myocardial relaxation
(E), isovolumetric relaxation time (IVRT), and myocardial performance index (MPI) at 4
and 8 weeks. Age matched wild type (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. While LV EF remained unchanged at 8 weeks, LVH and diastolic
dysfunction occurred with Wwp-1exp whereas an index of systolic function (MPI)
actually increased (Figure). LV mass increased by over 2-fold, E/A fell (impaired passive
filling), and E/E was lower and IVRT prolonged (impaired LV relaxation). Using targeted
PCR, myocardial matrix metalloproteinase-2 (MMP-2) increased in Wsp-1exp whereas
MMP-9 fell by 28% (p<0.05), indicative of a shift in the determinants of matrix
remodeling, similar to observations in patients with HFpEF.
Summary. Since changes in Wwp-1 have been identified with aging and the risk for
HFpEF increases as a function of age, the unique, new findings from this study provide
a potential mechanistic link for these past observations. Inducing Wwp-1 expression
caused LVH with significant diastolic dysfunction, consistent with the HFpEF phenotype.
Thus, targeting the Wwp-1 pathway may be a novel therapeutic target for this
intractable form of HF associated with aging.