Defining a Role for the Ubiquitin Ligase WWP1 in Cardiac Aging

With age, there is a gradual decline of cardiac structure and function, leading to increased susceptibility to heart failure. Approximately half the cases of heart failure are characterized by left ventricular (LV) hypertrophy and diastolic dysfunction without concomitant loss of contractility, classified as heart failure with preserved ejection fraction (HFpEF). At the cellular level, HFpEF is characterized by dysregulation of proteostasis and altered extracellular matrix dynamics. Ubiquitylation is a key post-translational modification that regulates protein turnover, and the expression of the E3 ubiquitin ligase WWP1 has been shown to increase with age. Thus, we hypothesized that deregulation of WWP1 in the heart can contribute to cardiac aging profiles. Global overexpression of WWP1 in mice promoted progressive LV hypertrophy over the first eight weeks of life as compared to referent control littermates. This was evidenced by a two-fold increase in LV mass and 1.5-fold increase in LV wall thickness by echocardiography (40MHz), accompanied by a statistically significant increase in cardiomyocyte fiber cross sectional surface area highlighted by wheat germ agglutinin staining of the sarcolemma and by reactivation of fetal growth genes Nppb, Nppa, and Myh7 as measured by real time PCR. Interestingly, this LV hypertrophy was not associated with any change in contractility as EF was preserved while diastolic function was compromised as indicated by Doppler velocities (early E, late/A), myocardial relaxation (E’), and isovolumetric relaxation time (IVRT), with significant decreases in passive filling (E/A), decreased E/E’, and impaired LV relaxation (prolonged IVRT). Additionally, overexpression of WWP1 promoted increased expression of fibrillar collagen mRNA and protein. In contrast, genetic ablation of Wwp1 in mice attenuated the 4-week response to LV pressure overload induced by transverse aortic constriction, with less LV hypertrophy, better indices of diastolic function, and less evidence of fibrosis than observed in WWP1 sufficient animals. In total, these data support the assertion that WWP1 levels contribute to the cardiac healthspan and that therapeutic modulation of this protein could be a viable strategy in HFpEF.